anticancer compounds

Abstract

The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof. The compounds of the present invention are BDII selective inhibitors of BET proteins and have therapeutic potential for the treatment of cancer, acute kidney disease and viral infections, among other diseases. [Formula 1] TIFF2024522588001168.tif98119

Description

Cross-reference of related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 208,191, filed on 8 June 2021. [Background technology]

[0002] Bromodomain and extraterminal domain (BET) family proteins are epigenetic readers that regulate gene transcription by binding to acetylated histones via their bromodomains. Because gene regulation is a crucial function for treating diseases such as cancer, BET family proteins have attracted considerable attention as drug targets. BET proteins bind to acetylated histones via their tandem bromodomains, BDI and BDII. Pan-BET (or pan-BET) inhibitors that bind to the BDI and BDII bromodomains of BRD2, BRD3, BRD4, and BRDt with similar affinity have shown moderate clinical activity in monotherapy cancer trials. Many pan-BET inhibitors are associated with dose-limiting adverse events such as thrombocytopenia and signs of gastrointestinal toxicity. 1-5 These adverse events may represent on-target activity related to pan-BET inhibition. Individual BET bromodomains may have different functions. 7-9 Different cellular phenotypes have been reported after pharmacological inhibition of one or both bromodomains. 10-11 This observation suggests that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared to pan-BET inhibitors. There is still a need to develop BET inhibitors that are selective for the BDII bromodomain. Such selective inhibitors could minimize on-target adverse effects while maintaining the therapeutic efficacy associated with pan-BET inhibitors. [Overview of the Initiative] [Means for solving the problem]

[0003] In some aspects, the present invention provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof: [Chemical formula] Wherein, K 1 to K 4 are each independently CH or N, provided that K 1 to K 4 at least one of which is CH; Ring B represents substituted or unsubstituted phenylene or 6-membered heteroarylene; Ring C represents substituted or unsubstituted arylene or heteroarylene; R 1 represents alkyl, alkenyl, haloalkyl, -O(alkyl), -S(alkyl), -NH(alkyl), or -N(alkyl)2; R x represents H, alkyl, or -C(O)alkyl; Alternatively, R 1 and R x , together with the intervening atoms, form an optionally substituted heterocycloalkyl ring, heterocycloalkenyl ring or heteroaryl ring; Each occurrence of R a is independently selected from the group consisting of halo, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, hydroxyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, haloalkoxy, heterocycloalkoxy, cyano, aryloxy, heteroaryloxy, and haloalkyl; Alternatively, the occurrences of R 1 and R a , together with the intervening atoms, form an optionally substituted heterocycloalkyl ring; Alternatively, the occurrences of R a and R x , together with the intervening atoms, form an optionally substituted heterocycloalkyl ring; J is -OH, -O(alkyl), -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl)2, -OCH2OC(O)O(alkyl), -NH2, -NHR j , or -CHF2; R j is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R b Each presence is independently selected from the group consisting of halo, oxo, alkyl, alkoxy, haloalkyl, cyano, cycloalkyl, aryl, aryloxy, -OH, -NH(alkyl), -C(O)H, -CO2(alkyl), and -CO2H; R c This represents a heterocycloalkyl, cycloalkyl, alkyl, aryl, heteroaryl, (heterocycloalkyl)alkyl, heterocycloalkenyl, alkoxy, alkynyl, aryloxy, haloalkyl, haloalkoxy, cycloalkoxy, or heterocycloalkoxy, or halo, -S(alkyl), -NH2, -CO2H, -CO2(alkyl), or -NHCO(alkyl); R i Each presence is independently selected from the group consisting of alkyl, haloalkyl, haloalkoxyl, alkoxyl, heterocycloalkyl, and cycloalkoxyl, which may be optionally substituted with halo, oxo, -S(alkyl), -NH2, -NH(alkyl), -N(alkyl)2, -OH, or cyano; Alternatively, R c and R i The presence of the intervening atom, together with the intervening atom, forms an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring which may be optionally substituted; Alternatively, R iThe presence of two adjacent atoms, together with the intervening atom, forms an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring which may be optionally substituted; m, n, and p are each independently 0, 1, or 2.

[0004] In a further embodiment, the present invention provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, K 1 ~K 4 Each is independently CH or N, except K 1 ~K 4 At least one of them is CH; Ring B represents a substituted or unsubstituted phenylene or a 6-membered heteroarylene; Ring C represents a substituted or unsubstituted arylene or a heteroarylene; R 1 is represented by alkyl, alkenyl, haloalkyl, -O(alkyl), -S(alkyl), -NH(alkyl), or -N(alkyl)2; R x represents H, alkyl, or -C(O)alkyl; Alternatively, R 1 and R x Together with the intervening atom, it forms a heterocycloalkyl ring, heterocycloalkenyl ring, or heteroaryl ring, which may be optionally substituted; R a Each presence is independently selected from the group consisting of halo, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, hydroxyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, haloalkoxy, heterocycloalkoxy, cyano, aryloxy, heteroaryloxy, and haloalkyl; Alternatively, R 1 and R aThe presence of the intervening atom forms a heterocycloalkyl ring, which may be optionally substituted; Alternatively, R a and R x The presence of the intervening atom forms a heterocycloalkyl ring, which may be optionally substituted; J is -OH, -O(alkyl), -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl)2, -OCH2OC(O)O(alkyl), -NH2, -NHR j , or -CHF2; R j is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R b Each of these is independently selected from the group consisting of halo, oxo, alkyl, alkoxy, haloalkyl, cyano, cycloalkyl, aryl, aryloxy, -OH, -NH(alkyl), -C(O)H, -CO2(alkyl), and -CO2H. R c represents H; R i Each presence is independently selected from the group consisting of alkyl, haloalkyl, haloalkoxyl, alkoxyl, heterocycloalkyl, and cycloalkoxyl, which may be optionally substituted with halo, oxo, -S(alkyl), -NH2, -NH(alkyl), -N(alkyl)2, -OH, or cyano; Alternatively, R i The presence of two adjacent atoms, together with the intervening atom, forms an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring which may be optionally substituted; m, n, and p are each independently 0, 1, or 2.

[0005] The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0006] Methods for treating or preventing cancer are also provided herein, which include administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof.

[0007] The present invention also comprises a method for treating a disease or condition, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the disease or condition is Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behçet's disease, bullous skin disease, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, dermatomyositis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, juvenile arthritis, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, childhood inflammatory multiple system syndrome, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis (or primary biliary cholangitis), psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, scleroderma, sclerosing cholangitis, The present invention provides a method selected from the group consisting of sepsis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, Takayasu's arteritis, toxic shock syndrome, thyroiditis, type 1 diabetes mellitus, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0008] Furthermore, this specification also provides a method for treating acquired immunodeficiency syndrome (AIDS), which includes administering a therapeutically effective amount of the compound of the present invention to a subject in need of treatment.

[0009] The present invention also provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the disease or condition is selected from the group consisting of obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes mellitus, insulin resistance, diabetic retinopathy, and diabetic neuropathy.

[0010] The present invention also provides a method for treating acute kidney disease, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the acute kidney disease or condition is selected from the group consisting of ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radioisotope induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, drug toxicity induced kidney disease, diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubular interstitial nephritis.

[0011] A method for treating fibrosis is also provided herein, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof.

[0012] In another embodiment, the present invention provides a method for treating an epithelial wound, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need of such treatment.

[0013] Methods for treating a viral infection, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the viral infection is caused by a DNA virus or an RNA virus. For example, the viral infection may be caused by an RNA virus of the Coronaviridae family, such as SARS-CoV or SARS-CoV-2.

[0014] In another embodiment, the present invention provides a method for selectively inhibiting bromodomain and extraterminal (BET) proteins in cells, comprising contacting cells with an effective amount of the compound of the present invention. [Modes for carrying out the invention]

[0015] definition The articles “a” and “an” are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the articles. For example, “element” means one or more elements.

[0016] The term "heteroatom" is recognized in the art and refers to an atom of any element other than carbon or hydrogen. Examples of heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or oxygen, nitrogen, or sulfur.

[0017] As used herein, the term “alkyl” is a term used in the art and refers to saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, linear or branched alkyl groups have about 30 or fewer carbon atoms in their skeleton (for example, C1-C for linear groups). 30 For branched chains, C3~C 30 ), or having approximately 20 or fewer carbon atoms, or 10 or fewer carbon atoms. In certain embodiments, the term "alkyl" means C1-C 10 Refers to alkyl groups. In certain embodiments, the term "alkyl" refers to C1-C6 alkyl groups, for example, C1-C6 linear alkyl groups. In certain embodiments, the term "alkyl" refers to C3-C 12This refers to branched alkyl groups. In certain embodiments, the term "alkyl" refers to C3-C8 branched alkyl groups. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0018] The term "cycloalkyl" refers to monocyclic, bicyclic, or bridging carbocyclic rings, each having 3 to 12 carbon atoms, which may be fully saturated or contain one or more unsaturated units; however, to avoid misunderstanding, the degree of unsaturation does not result in an aromatic ring system. Certain cycloalkyls may have 5 to 12 carbon atoms in their ring structure, or 6 to 10 carbon atoms in their ring structure. Preferably, cycloalkyls are (C3-C7) cycloalkyls representing monocyclic saturated carbocyclic rings having 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridging monocyclic rings and fused bicyclic rings. A bridging monocyclic ring includes a monocyclic cycloalkyl ring, where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., -(CH2) wThe rings are linked by a bridging group of the form -(wherein w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Condensed bicyclic cycloalkyl ring systems include monocyclic cycloalkyl rings condensed to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl. The bridging or condensed bicyclic cycloalkyl is bonded to the parent molecule via any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group may be optionally substituted. In certain embodiments, the condensed bicyclic cycloalkyl is a 5 or 6-membered monocyclic cycloalkyl ring condensed to a phenyl ring, a 5 or 6-membered monocyclic cycloalkyl, a 5 or 6-membered monocyclic cycloalkenyl, a 5 or 6-membered monocyclic heterocycloalkyl, or a 5 or 6-membered monocyclic heteroaryl, and the condensed bicyclic cycloalkyl is optionally substituted.

[0019] The "cycloalkenyl" group refers to a cycloalkyl group that has at least one more unsaturated unit, but to avoid misunderstanding, the degree of unsaturation does not result in an aromatic ring system.

[0020] The term "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a (cycloalkyl)alkyl group is the cyclohexylmethyl group.

[0021] The term "heterocycloalkyl," as used herein, refers to a radical of a non-aromatic ring system, including but not limited to monocyclic, bicyclic, and tricyclic rings, which are fully saturated or may contain one or more unsaturated units (but to avoid misunderstanding, the degree of unsaturation does not result in an aromatic ring system), and having 3 to 12 atoms, including at least one heteroatom such as nitrogen, oxygen, or sulfur. For illustrative purposes, which should not be construed as limiting the scope of the invention, the following are examples of heterocyclic rings: azilidinyl, azilinyl, oxylanyl, thyranyl, thyrenyl, dioxylanyl, diazilinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolidinyl, isothiazolidinyl, isoxazolidinyl Isooxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxop Loridinyl, piperadinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianil. Heterocycloalkyl groups are optionally substituted with one or more substituents listed below.

[0022] The term "(heterocycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

[0023] The "heterocycloalkenyl" group refers to a heterocycloalkyl group that has at least one more unsaturated unit, but to avoid misunderstanding, the degree of unsaturation does not result in an aromatic ring system.

[0024] As used herein, the term “alkenyl” means a linear or branched hydrocarbon radical containing 2 to 10 carbon atoms and at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Typical examples of alkenyls include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond of the alkenyl group can be located anywhere in its part and can have either a (Z) or (E) configuration around the double bond.

[0025] As used herein, the term "alkynyl" means a linear or branched hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Typical examples of alkynyls include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0026] The term "alkylene" is recognized in the art and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from an alkyl group as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents, such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluoromethyl), and cyanos. In one embodiment, "substituted alkyl" is "alkylene".

[0027] The term "amino" is a term used in the art and, as used herein, refers to both unsubstituted and substituted amines, for example, the portion that can be represented by the following general formula: [ka] In the formula, R a , R b , and R c These are, independently, hydrogen, alkyl, alkenyl, and -(CH2) x -R d It represents; or, R a and R b Together with the N atoms to which they are bonded, they complete a heterocycle having 4 to 8 atoms in the ring structure; R d x represents an aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl; x is zero or an integer in the range of 1 to 8. In certain embodiments, R a or R b One of them may be a carbonyl group, for example, R a , R b , and nitrogen do not form an imide together. In other embodiments, R a and R b (and R at the optional rate)c ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d It represents.

[0028] In certain embodiments, the term "amino" refers to -NH2.

[0029] In certain embodiments, the term "alkylamino" refers to -NH (alkyl).

[0030] In certain embodiments, the term "dialkylamino" refers to -N(alkyl)2.

[0031] The term "amide," as used herein, means -NHC(=O)-, where the amide group is bonded to the parent molecule via nitrogen. Examples of amides include alkylamides such as CH3C(=O)N(H)- and CH3CH2C(=O)N(H)-.

[0032] The term "acyl" is a term used in the art and, as used herein, refers to any group or radical of the form RCO- (wherein R is any organic group, e.g., alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl). Representative acyl groups include acetyl, benzoyl, and malonyl.

[0033] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0034] The term "aminoacyl" is a term used in the art and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0035] As used herein, the term "aminothionyl" refers to an analogue of an aminoacyl in which the oxygen atom of RC(O)- is substituted with sulfur, and therefore is in the form of RC(S)-.

[0036] The term "phosphoryl" is a term used in the art and, as used herein, can generally be represented by the following formula: [ka] In the formula, Q50 represents S or O, and R59 represents hydrogen, a lower alkyl, or an aryl; for example, -P(O)(OMe)- or -P(O)(OH)2. When used to substitute alkyls, for example, the phosphoryl group of a phosphorylalkyl can be represented by the following general formula: [ka] In the formula, Q50 and R59 are, independently, as defined above, and Q51 represents O, S, or N; for example, -OP(O)(OH)OMe or -NH-P(O)(OH)2. When Q50 is S, the phosphoryl portion is "phosphorothioate".

[0037] As used herein, the term "aminophosphoryl" refers to a phosphoryl group substituted with at least one amino group as defined herein; for example, -P(O)(OH)NMe2.

[0038] The term "azide" or "azido" as used herein refers to the -N3 group.

[0039] As used herein, the term "carbonyl" refers to -C(=O)-.

[0040] As used herein, the term "thiocarbonyl" refers to -C(=S)-.

[0041] As used herein, the term "alkylphosphoryl" refers to a phosphoryl group substituted with at least one alkyl group as defined herein; for example, -P(O)(OH)Me.

[0042] The term "alkylthio" as used herein refers to alkyl-S-. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0043] As used herein, the term "carboxyl" refers to the -CO2H group.

[0044] The term "aryl" is a term used in the art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains 6 to 10 carbon ring atoms (i.e., (C6-C)). 10 )aryl). The aromatic ring may be substituted at one or more ring positions with one or more substituents such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluoromethyl), cyanos, etc. The term “aryl” also includes polycyclic ring systems (the rings are “fused rings”) having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is an aromatic hydrocarbon, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. In certain embodiments, the term “aryl” refers to a phenyl group.

[0045] The term "arylene," as defined above, refers to a diradical obtained by removing two hydrogen atoms from an aryl group. In certain embodiments, arylene refers to a disubstituted arene, i.e., an arene substituted at two positions with substituents such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluoromethyl), or cyanos. In other words, in certain embodiments, "substituted aryl" is "arylene."

[0046] The term "phenylene" refers to a diradical obtained by removing two hydrogen atoms from benzene. An example of a phenylene group is the following structure: [ka]

[0047] The term "heteroaryl" is a term used in the art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms, including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl (e.g., imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, and imidazo[1,5-azipyridinyl]), indolyl, indolinyl, indolidinyl, indazolyl, isoindolinyl, iso Examples include xazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, prinyl, pyranyl, pyrazinyl, pyrazolyl, pyridadinyl, pyridinyl, 2-pyridonyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetraazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanil. A "heteroaryl" may be substituted at one or more ring positions with one or more substituents such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluoromethyl), and cyanos. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings (the rings are "fused rings") in which two or more carbons are common to two adjacent rings, and at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls.The term "heteroaryl" also includes 2-pyridone, which is a tautomer of 2-hydroxypyridine.

[0048] The term "heteroarylene," as defined above, refers to a diradical obtained by removing two hydrogen atoms from a heteroaryl group. In certain embodiments, heteroarylene refers to a disubstituted heteroarene, i.e., a heteroarene substituted at two positions with substituents such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluoromethyl), or cyanos. In other words, in certain embodiments, "substituted heteroaryl" is "heteroarylene."

[0049] The terms "aralkyl" or "arylalkyl" are terms used in the art and, as used herein, refer to an alkyl group substituted with an aryl group, which is attached to the parent molecule via the alkyl group.

[0050] The terms "heteroaralkyl" or "heteroarylalkyl" are terms used in the art and, as used herein, refer to an alkyl group substituted with a heteroaryl group that is added to the parent molecule via an alkyl group.

[0051] As used herein, the term "alkoxy" means an alkyl group as defined herein, which is added to the parent molecule via an oxygen atom. Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0052] The term "alkoxyalkyl" refers to an alkyl group that has been substituted with an alkoxy group.

[0053] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, that is attached to the parent molecule via a carbonyl group represented by -C(=O)- as defined herein. Typical examples of alkoxycarbonyls include, but are not limited to, methoxycarbonyls, ethoxycarbonyls, and tert-butoxycarbonyls.

[0054] As used herein, the term “alkylcarbonyl” means an alkyl group as defined herein that is added to the parent molecule via a carbonyl group as defined herein. Typical examples of alkylcarbonyls include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0055] As used herein, the term “arylcarbonyl” means an aryl group as defined herein that is added to the parent molecule via a carbonyl group as defined herein. Typical examples of arylcarbonyls include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0056] The terms “alkylcarbonyloxy” and “arylcarbonyloxy,” as used herein, mean an alkylcarbonyl or arylcarbonyl group, as defined herein, that is added to the parent molecule via an oxygen atom. Typical examples of alkylcarbonyloxys include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Typical examples of arylcarbonyloxys include, but are not limited to, phenylcarbonyloxy.

[0057] The term "alkenoxy" or "alkenoxyl" means an alkenyl group, as defined herein, that is added to the parent molecule via an oxygen atom. Typical examples of alkenoxyls include, but are not limited to, 2-propene-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-).

[0058] As used herein, the term “aryloxy” means an aryl group as defined herein, which is added to the parent molecule via an oxygen atom.

[0059] As used herein, the term “heteroaryloxy” means a heteroaryl group as defined herein, which is added to the parent molecule via an oxygen atom.

[0060] The term "carbocyrill," as used herein, means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms that is fully saturated or has one or more unsaturated bonds, and to avoid misunderstanding, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyrill groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0061] The term "cyano" is a term used in this art and, as used herein, refers to -CN.

[0062] The term "halo" is a term used in the art and, as used herein, refers to -F, -Cl, -Br, or -I.

[0063] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, in which some or all of the hydrogen atoms are substituted with halogen atoms.

[0064] The term "hydroxyl" is a term used in this art and, as used herein, refers to -OH.

[0065] As used herein, the term “hydroxyalkyl” means that at least one hydroxyl group, as defined herein, is attached to the parent molecule via an alkyl group, as defined herein. Typical examples of hydroxyalkyls include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0066] The term “silyl,” as used herein, includes hydrocarbyl derivatives of the silyl (H3Si-) group (i.e., (hydrocarbyl)3Si-), where the hydrocarbyl group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, such as ethyl or phenyl. The hydrocarbyl group may be a different combination of groups that can be modified to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0067] The term "silyloxy," as used herein, means a silyl group as defined herein, which is added to the parent molecule via an oxygen atom.

[0068] Certain compounds included in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Furthermore, the compounds of the present invention may be optically active. The present invention intends to include all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, within the scope of the invention. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0069] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by induction using a chiral auxiliary agent. The resulting diastereomer mixture is then separated, the auxiliary groups are cleaved, and the pure, desired enantiomer is obtained. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt is formed using a suitable optically active acid or base, and the formed diastereomer is subsequently separated by fractional crystallization or chromatographic means known in the art, after which the pure enantiomer is recovered.

[0070] It will be understood that “substitution” or “substituted with” implies the implicit condition that such substitution follows the allowable valencies of the substituted atom and substituent, as well as the implicit condition that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reactions.

[0071] The term “substituted” is also intended to include all permissible substituents of an organic compound. In a broader embodiment, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents are, for example, those described herein. There may be one or more permissible substituents, and they may be the same or different for a given organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have any permissible substituent of the organic compound described herein that satisfies the hydrogen substituent and / or the valence of the heteroatom. The present invention is not intended to be limited in any way by permissible substituents of an organic compound.

[0072] "Deuterium-substituted" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0073] In certain embodiments, the compounds of the present invention are substituted with deuterium. For example, in an alkyl group, one or more hydrogen atoms may be replaced by a corresponding number of deuterium atoms.

[0074] It is recognized that some variation in the natural isotopic abundance occurs in the synthesized compounds, depending on the origin of the chemicals used in the synthesis. Therefore, the preparations of the compounds of the present invention contain essentially small amounts of deuterated isotopologues. The concentrations of naturally abundant stable isotopes of hydrogen and carbon, regardless of this variation, are small and insignificant compared to the degree of stable isotopic substitution in the deuterium compounds of the present invention.

[0075] In the compounds of the present invention, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. The stable isotopes of hydrogen are: 1 H (light hydrogen or protium) and 2This is H (deuterium). Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to contain hydrogen in its naturally occurring isotopic composition. Also, unless otherwise specified, when a position is specifically designated as "D" or "deuterium", that position is understood to contain deuterium at an abundance at least 3340 times higher than the naturally occurring abundance of deuterium, which is 0.015% (i.e., at least 50.1% of deuterium incorporated).

[0076] In certain embodiments, any substituent may be, for example, halogens, alkyl halogens (e.g., fluoroalkyl or trifluoromethyl), hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetic acid (thioacetate), or thioformate (thioformate)), alkoxyl, alkenyloxy, alkynyloxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (including alkyl and dialkylamino), amide, amidine, imine, or shea May contain no, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, silyl, silyloxy, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkoxy, heterocycloalkoxy, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyl, or heteroaralkyl groups.

[0077] As used herein, the term "protecting group" refers to a transient substituent that protects a potentially reactive functional group from undesirable chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry is outlined (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2 nd (ed.; Wiley: New York, 1991). The protected forms of the compounds of the present invention are included within the scope of the present invention.

[0078] For the purposes of this invention, chemical elements are identified according to the periodic table on the inside cover of Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0079] Other chemical terms used herein are used in accordance with their prior art usage, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains.

[0080] As used herein, the term “pharmaceutically acceptable salt” includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. A pharmaceutically acceptable salt form may include forms in which the ratio of molecules containing the salt is not 1:1. For example, a salt may contain more than one inorganic or organic acid molecule per base molecule, such as two hydrochloric acid molecules per molecule of compound of formula (I). Another example is a salt which may contain less than one inorganic or organic acid molecule per base molecule, such as two molecules of compound of formula (I) per molecule of tartaric acid.

[0081] The terms “carrier” and “pharmaceutically acceptable carrier,” as used herein, refer to diluents, adjuvants, excipients, or vehicles used with a compound to administer or formulate it for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oil; as well as solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, and urea. In addition, auxiliaries, stabilizers, thickeners, lubricants, flavorings, and colorants may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, which is incorporated herein by reference in its entirety.

[0082] As used herein, the term “treat” means to prevent, halt, slow the progression of, or eliminate a disease or condition in a subject. In one embodiment, “treat” means to halt or slow the progression of a disease or condition in a subject, or to eliminate the disease or condition. In one embodiment, “treat” means to mitigate at least one objective sign of a disease or condition in a subject.

[0083] As used herein, the term "effective dose" refers to an amount sufficient to produce the desired biological effect.

[0084] As used herein, the term "therapeutic dose" refers to an amount sufficient to produce the desired therapeutic effect.

[0085] As used herein, the term “inhibit” means a reduction by an objectively measurable amount or degree. In various embodiments, “inhibit” means a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to the relevant control. In one embodiment, “inhibit” means a 100 percent reduction, i.e., cessation or elimination.

[0086] As used herein, the term “subject” refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cattle, or non-human primate. In certain embodiments, the subject is a human.

[0087] compound In certain embodiments, the present invention provides compounds having the structure of formula (I) or pharmaceutically acceptable salts thereof: [ka] During the ceremony, K 1 ~K 4 Each is independently CH or N, except K 1 ~K 4 At least one of them is CH; Ring B represents a substituted or unsubstituted phenylene or a 6-membered heteroarylene; Ring C represents a substituted or unsubstituted arylene or a heteroarylene; R 1 is represented by alkyl, alkenyl, haloalkyl, -O(alkyl), -S(alkyl), -NH(alkyl), or -N(alkyl)2; R x represents H, alkyl, or -C(O)alkyl; Alternatively, R 1 and R x Together with the intervening atom, it forms a heterocycloalkyl ring, heterocycloalkenyl ring, or heteroaryl ring, which may be substituted; R a Each presence is independently selected from the group consisting of halo, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, hydroxyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, haloalkoxy, heterocycloalkoxy, cyano, aryloxy, heteroaryloxy, and haloalkyl; Alternatively, R 1 and R a The presence of the intervening atom forms a heterocycloalkyl ring, which may be optionally substituted; Alternatively, R a and R x The presence of the intervening atom forms a heterocycloalkyl ring, which may be optionally substituted; J is -OH, -O(alkyl), -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl)2, -OCH2OC(O)O(alkyl), -NH2, -NHR j , or -CHF2; R j is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R b Each presence is independently selected from the group consisting of halo, oxo, alkyl, alkoxy, haloalkyl, cyano, cycloalkyl, aryl, aryloxy, -OH, -NH(alkyl), -C(O)H, -CO2(alkyl), and -CO2H; R crepresents heterocycloalkyl, cycloalkyl, alkyl, aryl, heteroaryl, (heterocycloalkyl)alkyl, heterocycloalkenyl, alkoxyl, alkynyl, aryloxy, haloalkyl, haloalkoxyl, cycloalkoxyl or heterocycloalkoxyl, each of which is optionally substituted, or represents halo, S(alkyl), -NH₂, -CO₂H, -CO₂(alkyl) or -NHCO(alkyl); R i each occurrence of is independently halo, oxo, -S(alkyl), -NH₂, -NH(alkyl), -N(alkyl)₂, -OH, or cyano, or is independently selected from the group consisting of optionally substituted alkyl, haloalkyl, haloalkoxyl, alkoxyl, heterocycloalkyl, and cycloalkoxyl; Alternatively, R c and R i together with the intervening atoms form an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring; Alternatively, R i two adjacent occurrences of together with the intervening atoms form an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring; m, n and p are each independently 0, 1 or 2.

[0088] In a specific embodiment of the compound of formula (I), K 1 to K 4 are each independently CH or N, provided that at least one of K 1 to K 4 is CH; Ring B represents substituted or unsubstituted phenylene or 6-membered heteroarylene; Ring C represents substituted or unsubstituted arylene or heteroarylene; R 1 represents alkyl, alkenyl, haloalkyl, -O(alkyl), -S(alkyl), -NH(alkyl), or -N(alkyl)₂; R x represents H, alkyl, or -C(O)alkyl; alternatively, R 1 and R x , together with the intervening atoms, form an optionally substituted heterocycloalkyl ring, heterocycloalkenyl ring, or heteroaryl ring; R a each occurrence is independently selected from the group consisting of halo, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, alkyl, alkoxy, cycloalkoxy, haloalkoxy, heterocycloalkoxy, cyano, aryloxy, heteroaryloxy, and haloalkyl; alternatively, R 1 and R a , together with the intervening atoms, form an optionally substituted heterocycloalkyl ring; alternatively, R a and R x , together with the intervening atoms, form an optionally substituted heterocycloalkyl ring; J represents -OH, -O(alkyl), -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl)2, -OCH2OC(O)O(alkyl), -NH2, -NHR j , or -CHF2; R j is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R b each occurrence is independently selected from the group consisting of halo, alkyl, alkoxyl, cyano, cycloalkyl, aryl, aryloxy, -CO2(alkyl), and -CO2H; R crepresents a heterocycloalkyl, cycloalkyl, alkyl, aryl, heteroaryl, alkoxyl, alkynyl, aryloxy, haloalkyl, haloalkoxy, cycloalkoxyl, or heterocycloalkoxyl, or halo, -S(alkyl), -NH2, -CO2H, -CO2(alkyl), or -NHCO(alkyl); R i Each presence is independently selected from the group consisting of alkyl, haloalkyl, haloalkoxyl, alkoxyl, heterocycloalkyl, and cycloalkoxyl, which may be halo, oxo, -S(alkyl), or cyano, or optionally substituted; Alternatively, R c and R i The presence of the intervening atom, together with the intervening atom, forms an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring which may be optionally substituted; Alternatively, R i The presence of two adjacent atoms, together with the intervening atom, forms an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring; m, n, and p are each independently 0, 1, or 2.

[0089] In a particular embodiment, K 1 ~K 4 These are CH respectively. In such an embodiment, K 1 ~K 4 Any one or more hydrogen atoms of the CH group are optionally R a It is replaced by the presence of [something].

[0090] For example, the compound of the present invention may have the structure of formula (Ia): [ka]

[0091] In a particular embodiment, m is 0.

[0092] In certain embodiments, m is 1. For example, the compound of the present invention may have the structure of formula (Iai): [ka]

[0093] In certain embodiments, m is 2. For example, the compound of the present invention may have the structure of formula (Iaii): [ka]

[0094] In a particular embodiment, K 1 ~K 4 One of them is N, and K 1 ~K 4 The remainder is CH. In such embodiments, K 1 ~K 4 Any one or more hydrogen atoms of the CH group are optionally R a It is replaced by the presence of [something].

[0095] For example, in certain such embodiments, K 1 is N. In an alternative such embodiment, K 2 It is N.

[0096] In a particular embodiment, K 1 ~K 4 Two of them are N, and K 1 ~K 4 The remainder is CH. In such embodiments, K 1 ~K 4 Any one or more hydrogen atoms of the CH group are optionally R a It is replaced by the presence of [something].

[0097] For example, in a particular embodiment, K 1 and K 3 is N. In an alternative embodiment, K 1 and K4 It is N. Or, K. 1 and K 2 It may also be N.

[0098] In certain embodiments, ring B represents a substituted or unsubstituted phenylene (i.e., a six-membered carbocyclic aromatic ring). For example, the compounds of the present invention may have the structure of formula (Ib): [ka]

[0099] In certain embodiments, ring C occupies the ortho position relative to group J. For example, the compounds of the present invention may have the structure of formula (Ibi): [ka]

[0100] In certain such embodiments, n is 1. For example, the compound of the present invention may have the structure of formula (Ibii): [ka]

[0101] In other embodiments, n is 0. For example, the compound of the present invention may have the structure of formula (Ibiii): [ka]

[0102] In certain embodiments, ring B represents a substituted or unsubstituted six-membered heteroarylene. In certain such embodiments, the compound has the structure of formula (Ibh): [ka] In the formula, K 5 ~K 8 Each is independently selected from CH and N, and K 5~K 8 At least one of them is N.

[0103] For example, in some embodiments, K 6 It is N.

[0104] In a particular embodiment, K 5 ~K 8 One of them is N. In another embodiment, K 5 ~K 8 Two of them are N.

[0105] In certain embodiments, ring B represents a substituted or unsubstituted pyridine. In certain such embodiments, the compound has the structure of formula (Ibhi): [ka]

[0106] In certain embodiments, ring C occupies the ortho position relative to group J. For example, the compounds of the present invention may have the structure of formula (Ibhii): [ka]

[0107] In certain such embodiments, n is 1. For example, the compound of the present invention may have the structure of formula (Ibhiii): [ka]

[0108] In other embodiments, n is 0. For example, the compound of the present invention may have the structure of formula (Ibhiv): [ka]

[0109] In some embodiments, ring C represents a substituted or unsubstituted heteroarylene, for example, a substituted or unsubstituted five-membered heteroarylene. For example, ring C may be a substituted or unsubstituted 1,2-oxazole, 1,2-thiazole, 1,2-diazole, 1,3-oxazole, 1,3-thiazole, 1,3-diazole, or 1,3,4-triazole.

[0110] Alternatively, in some embodiments, ring C is a substituted or unsubstituted bicyclic heteroarylene group.

[0111] Alternatively, in some embodiments, ring C represents a substituted or unsubstituted six-membered arylene (i.e., phenylene) or a six-membered heteroarylene.

[0112] In certain such embodiments, R on ring C c The substituent is located in the meta position relative to ring B.

[0113] Therefore, in certain embodiments, the compound has the structure of formula (Icm): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0114] In certain such embodiments, ring C represents substituted or unsubstituted phenylene (i.e., both X and Y are CH). Thus, in some embodiments, the compounds of the present invention have the structure of formula (Icmi): [ka]

[0115] In other such embodiments, ring C represents a substituted or unsubstituted six-membered heteroarylene (for example, one of X and Y is N). Thus, in some embodiments, the compounds of the present invention have the structure of formula (Icmii): [ka]

[0116] In other embodiments, the compound of the present invention has the structure of formula (Icmiii): [ka]

[0117] In other embodiments, R on ring C c The substituent is located in the para position relative to ring B.

[0118] Therefore, in certain embodiments, the compound has the structure of formula (Icp): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0119] In certain such embodiments, ring C represents a substituted or unsubstituted phenylene (i.e., both X and Y are CH). Thus, in some embodiments, the compounds of the present invention have the structure of formula (Icpi): [ka]

[0120] In other such embodiments, ring C represents a substituted or unsubstituted six-membered heteroarylene (for example, one of X and Y is N). Thus, in some embodiments, the compounds of the present invention have the structure of formula (Icpii): [ka]

[0121] In other embodiments, the compound of the present invention has the structure of formula (Icpiii): [ka]

[0122] In other embodiments, R on ring C c The substituent is in the ortho position relative to ring B.

[0123] Therefore, in certain embodiments, the compound has the structure of formula (Ico): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0124] In certain such embodiments, ring C represents a substituted or unsubstituted phenylene (i.e., both X and Y are CH). Thus, in some embodiments, the compounds of the present invention have the structure of formula (Icoi): [ka]

[0125] In other such embodiments, ring C represents a substituted or unsubstituted six-membered heteroarylene (for example, one of X and Y is N). Thus, in some embodiments, the compounds of the present invention have the structure of formula (Icoii): [ka]

[0126] In other embodiments, the compounds of the present invention have the structure of formula (Icoiii): [ka]

[0127] In a particular embodiment, the compound of the present invention has the structure of formula (Ie): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0128] In certain such embodiments, the compound of the present invention has the structure of formula (Iei): [ka]

[0129] Alternatively, in some embodiments, the compounds of the present invention have the structure of formula (Ieii): [ka]

[0130] In further embodiments, the compound of the present invention has the structure of formula (Ieiii): [ka]

[0131] In further embodiments, the compounds of the present invention have the structure of formula (Ieu): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0132] In a specific alternative embodiment where the B ring is pyridine, the compound of the present invention has the structure of formula (If): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0133] In certain such embodiments, the compound of the present invention has the structure of formula (Ifi): [ka]

[0134] Alternatively, the compound may have the structure of formula (Ifii): [ka]

[0135] In other alternative embodiments, the compound of the present invention has the structure of formula (Ifiii): [ka]

[0136] In a specific alternative embodiment where the B ring is pyridine, the compound of the present invention has the structure of formula (Ifu): [ka] In the formula, X and Y are independently selected from CH and N, and at least one of X and Y is CH.

[0137] In certain embodiments, ring C represents a substituted or unsubstituted 2-pyridone.

[0138] For example, in a particular embodiment, the compound has the structure of formula (Igi): [ka]

[0139] In certain such embodiments, the nitrogen of pyridone is R i It is substituted with. For example, the compound of the present invention may have the structure of formula (Igia): [ka]

[0140] In certain such embodiments, rings A and B are phenylene rings, and the compound of the present invention has the structure of formula (Igib): [ka]

[0141] In an alternative embodiment, the compound of the present invention has the structure of formula (Igii): [ka]

[0142] In certain such embodiments, rings A and B are phenylene rings, and the compound of the present invention has the structure of formula (Igiia): [ka]

[0143] In an alternative embodiment, the compound of the present invention has the structure of formula (Igiii): [ka]

[0144] In certain such embodiments, the nitrogen of pyridone is R i It is substituted with. For example, the compound of the present invention may have the structure of formula (Igiiia): [ka]

[0145] In certain such embodiments, rings A and B are phenylene rings, and the compound of the present invention has the structure of formula (Igiiib): [ka]

[0146] In a particular embodiment, R 1 represents alkyl.

[0147] In a particular embodiment, R 1 (C1~C6) alkyl represents at least one hydrogen atom ( 1 H) is deuterium ( 2 It can be replaced with H or D.

[0148] In further embodiments, R 1 and R x Together with the intervening atom, it forms a heterocycloalkyl ring, a heterocycloalkenyl ring, or a heteroaryl ring, which may be optionally substituted.

[0149] In a particular embodiment, R 1 and R x Together with the intervening atom, it forms a heterocycloalkyl ring, a heterocycloalkenyl ring, or a heteroaryl ring, where the ring is substituted with alkyl. In some embodiments, at least one hydrogen atom of the alkyl substituent ( 1 H) is deuterium ( 2 Replaced by H or D)

[0150] In certain such embodiments, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0151] In further such embodiments, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0152] In further embodiments, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0153] In further embodiments, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0154] In some embodiments, m is 1.

[0155] In certain such embodiments, R a is a halo, alkyl, alkoxy, or cycloalkoxy. For example, R a This could be a halo, for example, fluoro or chloro.

[0156] In other embodiments, m is 2.

[0157] In certain such embodiments, R a R is independently a halo, alkyl, alkoxy, or cycloalkoxy. In some embodiments, R a At least one of them is a halo; for example, R a At least one of them is either fluoro or chloro.

[0158] In certain embodiments, J represents -OH or -NH2. For example, J may be -OH.

[0159] In other embodiments, J represents an -O- bond to the prodrug moiety. For example, J may be -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl)2, or -OCH2OC(O)O(alkyl).

[0160] In a particular embodiment, n is 0.

[0161] Alternatively, n may be 1. In certain such embodiments, R b is either halo or methyl. For example, R b This could be a halo, for example, an fluorophore.

[0162] In certain embodiments, p is 0. Alternatively, p may be 1. In certain such embodiments, R i It is alkyl or alkoxyl.

[0163] In a particular embodiment, R c R represents a heterocycloalkyl group which may be optionally substituted. For example, in some embodiments, R c This can represent piperazinil, piperidinil, morpholinil, pyrrolidinil, azepanil, 3,8-diazabicyclo[3.2.1]octanil, or 2,6-diazaspiro[3.3]heptanil, which may be optionally substituted.

[0164] In further embodiments, R c represents piperazinyl, piperidinyl, or pyrrolidinyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of amino, alkylamino, aminoalkyl, alkyl, alkoxyalkyl, halo, oxo, hydroxyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, amide, and alkoxyl.

[0165] For example, R cThis can represent an alkyl-substituted piperazinyl.

[0166] Exemplary R c The following are some examples, but are not limited to: [ka] [ka] [ka] [ka] [ka]

[0167] Exemplary compounds of the present invention include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0168] Further exemplary compounds of the present invention include: [ka] [ka] [ka] [ka] [ka] [ka]

[0169] Further exemplary compounds of the present invention include: [ka] [ka] [ka]

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[0170] Further exemplary embodiments include the following, which may be synthesized according to the synthesis procedures described in detail in this application: [ka]

[0171] In other embodiments, the compound is having the structure of formula (II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, K 1 ~K 4 Each is independently CH or N, except K 1 ~K 4 At least one of them is CH; Ring B represents a substituted or unsubstituted phenylene or a 6-membered heteroarylene; Ring C represents a substituted or unsubstituted arylene or a heteroarylene; R 1 is represented by alkyl, alkenyl, haloalkyl, -O(alkyl), -S(alkyl), -NH(alkyl), or -N(alkyl)2; R x represents H, alkyl, or -C(O)alkyl; Alternatively, R 1 and R x Together with the intervening atom, it forms a heterocycloalkyl ring, heterocycloalkenyl ring, or heteroaryl ring, which may be optionally substituted; R a Each presence is independently selected from the group consisting of halo, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, hydroxyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, haloalkoxy, heterocycloalkoxy, cyano, aryloxy, heteroaryloxy, and haloalkyl; Alternatively, R 1 and R a The presence of the intervening atom forms a heterocycloalkyl ring, which may be optionally substituted; Alternatively, R a and R x The presence of the intervening atom forms a heterocycloalkyl ring, which may be optionally substituted; J is -OH, -O(alkyl), -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl)2, -OCH2OC(O)O(alkyl), -NH2, -NHR j , or -CHF2; R j is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R b Each presence is independently selected from the group consisting of halo, oxo, alkyl, alkoxy, haloalkyl, cyano, cycloalkyl, aryl, aryloxy, -OH, -NH(alkyl), -C(O)H, -CO2(alkyl), and -CO2H; R c represents H; R iEach presence is independently selected from the group consisting of alkyl, haloalkyl, haloalkoxyl, alkoxyl, heterocycloalkyl, and cycloalkoxyl, which may be optionally substituted with halo, oxo, -S(alkyl), -NH2, -NH(alkyl), -N(alkyl)2, -OH, or cyano; Alternatively, R i The presence of two adjacent atoms, together with the intervening atom, forms an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring; m, n, and p are each independently 0, 1, or 2.

[0172] In a particular embodiment, K 1 ~K 4 Each of them is CH.

[0173] In a particular embodiment, m is 1, and R a It is a halo.

[0174] In certain embodiments, ring B represents a substituted or unsubstituted phenylene.

[0175] In a particular embodiment, n is 0.

[0176] In certain embodiments, J is OH.

[0177] In a particular embodiment, R x represents H. In a particular embodiment, R 1 It is alkyl.

[0178] Alternatively, R 1 and R x Together with the intervening atom, it may form a heterocycloalkyl ring, a heterocycloalkenyl ring, or a heteroaryl ring, which may be optionally substituted.

[0179] In a particular embodiment, the compound of formula (II) is selected from the following table: [ka] [ka] [ka]

[0180] Pharmaceutical composition The present invention provides pharmaceutical compositions each comprising one or more compounds of the present invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises the compounds of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0181] The pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutically active agents.

[0182] How to use The present invention provides compounds useful for treating or preventing diseases or conditions in which treatment would benefit from selective inhibition of BDII, and pharmaceutically acceptable salts thereof.

[0183] Bromodomain and extraterminal domain (BET) family proteins regulate gene transcription through interaction with specific acetylated lysine at histone H3 and H4 tails. At these sites, these BET proteins recruit key components of the transcription mechanism, thereby enabling them to control the host of disease-centric gene expression programs, such as cancer. These BET proteins bind to acetylated histone tails via their two tandem bromodomains, BDI and BDII. Unfortunately, pan-BET inhibitors have shown on-target toxicity, including thrombocytopenia, anemia, neutropenia, and severe gastrointestinal events. However, selective inhibition of the BDII bromodomain offers therapeutic efficacy while minimizing undesirable toxicity.

[0184] The compounds of the present invention inhibit the binding of the second bromodomain (BDII) of BRD2, BRD3, BRD4, and BRDt to their cellular targets. This function effectively alters the expression of genes essential for the growth of certain cancers, such as acute myeloid leukemia and prostate cancer.

[0185] In certain embodiments, the present invention provides a method for treating or preventing cancer, comprising administering a therapeutically effective amount of the compound of the present invention (for example, a compound of formula (I)) to a subject in need thereof.

[0186] In one embodiment, cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, myelomonocytic and promyelocytic), acute T-cell leukemia, adrenocortical carcinoma, anal cancer, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain tumor, breast cancer, bronchogenic carcinoma, carcinosarcoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, clear cell carcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, fibroplastic round cell tumor, diffuse large B-cell lymphoma, dysproliferative changes (dysproliferative changes) Change (dysplasia and metaplasia), fetal cancer, endometrial cancer, endometrial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, gallbladder cancer, gastric cancer, germ cell testicular tumor Cancer, glioma, glioblastoma, gliosarcoma, hairy cell leukemia, heavy chain disease, hemangioblastoma, liver cancer (hepatoma), hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, lipogenic sarcoma, lymphoma, malignant peripheral nerve sheath tumor, medullary carcinoma, mantle cell lymphoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma.Myelodysplastic syndrome, myeloproliferative disorders, myelofibrosis, mucoepidermoid carcinoma, myxoid neoplasm, myxosarcoma, neuroblastoma, NUT midline carcinoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pheochromocytoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, reticulum cell sarcoma, retinoblastoma, rhabdomyosarcoma, salivary ductal carcinoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), squamous cell carcinoma, synovial sarcoma, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, endometrial cancer, and Wilms' tumor.

[0187] In further embodiments, the present invention provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of a compound of the present invention, for example, a compound of formula (I), to a subject in need thereof, wherein the disease or condition is Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behçet's disease, bullous skin disease, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, dermatomyositis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, juvenile arthritis, Kawasaki disease, lupus nephritis, multiple sclerosis, heart disease, etc. The present invention provides a method for selecting from the group consisting of myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, childhood inflammatory multiple system syndrome, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis (or primary biliary cholangitis), psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, scleroderma, sclerosing cholangitis, sepsis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, Takayasu's arteritis, toxic shock syndrome, thyroiditis, type 1 diabetes mellitus, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0188] In further embodiments, the present invention provides a method for treating acquired immunodeficiency syndrome (AIDS), comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof.

[0189] In further embodiments, the present invention provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the disease or condition is selected from the group consisting of obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes mellitus, insulin resistance, diabetic retinopathy, and diabetic neuropathy.

[0190] In further embodiments, the present invention provides a method for treating acute kidney disease, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the acute kidney disease or condition is selected from the group consisting of ischemia-reperfusion-induced kidney disease, cardiac and major surgery-induced kidney disease, percutaneous coronary intervention-induced kidney disease, radiocontrast-induced kidney disease, sepsis-induced kidney disease, pneumonia-induced kidney disease, drug toxicity-induced kidney disease, diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubulointerstitial nephritis.

[0191] The present invention also provides a method for treating fibrosis, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof. Fibrosis may be, for example, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, or cardiac fibrosis.

[0192] The present invention also provides a method for treating an epithelial wound, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof. Epithelial wounds may be, for example, surgical wounds, burns, abrasions, ulcers, or diabetic wounds, wounds caused by cancer, wounds caused by infectious diseases, or wounds caused by inflammatory diseases.

[0193] The present invention also provides a method for treating a viral infection, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need thereof, wherein the viral infection is caused by a DNA virus or an RNA virus.

[0194] In certain embodiments, the DNA virus is selected from the group of viridae families consisting of Adenoviridae, Papovaviridae, Parvoviridae, Herpesviridae, Poxviridae, Anelloviridae, and Pleolipoviridae.

[0195] In certain embodiments, the RNA virus is selected from the group of viridae families consisting of Reovirida, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Coronaviridae, Astroviridae, Bornaviridae, Arteriviridae, and Hepeviridae. Preferably, the viral infection is caused by an RNA virus of the Coronaviridae family. In such embodiments, the viral infection is SARS-CoV or SARS-CoV-2.

[0196] In further embodiments, the present invention provides a method for selectively inhibiting bromodomain and extraterminal (BET) proteins in cells, comprising contacting the cells with an effective amount of the compound of the present invention. The cells may be found in the body of a mammal, for example, in the body of a human.

[0197] In certain embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use as pharmaceuticals.

[0198] Formulation, route of administration, and medication The compounds of the present invention and their pharmaceutically acceptable salts can be formulated as pharmaceutical compositions and administered to mammalian hosts such as human patients in various forms suitable for selected routes of administration (e.g., orally or parenterally, via intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes). Further routes of administration are also conceived by the present invention.

[0199] Therefore, the compound or a pharmaceutically acceptable salt thereof may be administered systemically (e.g., orally) in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an absorbable food carrier. They may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the active compound (i.e., the compound of the present invention or a pharmaceutically acceptable salt thereof) may be used in combination with one or more excipients in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary and may conveniently be about 2% to about 60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dose level is obtained.

[0200] Tablets, lozenges, pills, capsules, etc., may also contain the following diluents and carriers: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring. If the unit dosage form is a capsule, in addition to the above types of materials, a liquid carrier such as vegetable oil or polyethylene glycol may be included. Various other materials may be present as coatings or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. Syrups or elixirs may contain active compounds, sucrose or fructose as sweeteners, methyl and propylparabens as preservatives, dyes, and flavoring agents such as cherry or orange flavor. Naturally, any materials used in preparing any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts used. Furthermore, active compounds can be incorporated into sustained-release preparations and devices.

[0201] The active compound may also be administered intravenously or intraperitoneally by injection or infusion. Solutions of the active compound can be prepared in water or a physiologically acceptable aqueous solution, sometimes mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, as well as in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0202] Pharmaceutical dosage forms suitable for injection or infusion may optionally include sterile aqueous solutions or dispersions or sterile powders containing active compounds adapted for immediate preparation of sterile injection or infusion solutions or dispersions encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid, and stable under manufacturing and storage conditions. The liquid carrier or vehicle may be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by liposome formation, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. Prevention of microbial action can be provided by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Sustained absorption of an injectable composition can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0203] Sterile injectable solutions are prepared by incorporating the required amount of active compound, along with various other components listed above as needed, into a suitable solvent, followed by sterilization by filtration. For sterile powders used in the preparation of sterile injectable solutions, the preparation method may include vacuum drying and freeze-drying techniques, which result in a powder of the active compound and any further desired components present in the pre-sterilized filtered solution.

[0204] For topical administration, the compound or any pharmaceutically acceptable salt thereof may be applied in pure form if they are liquids. However, it is generally preferable to administer it to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which may be solid or liquid.

[0205] Useful solid carriers include fine powders such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol or glycol, or water-alcohol / glycol blends, in which the compound or its pharmaceutically acceptable salts can be dissolved or dispersed at an effective level, sometimes with the help of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid composition can be applied from an absorbent pad, impregnated into bandages and other dressings, or sprayed onto the affected area using a pump or aerosol sprayer.

[0206] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral materials can also be used with liquid carriers to form applicable pastes, gels, ointments, soaps, etc., for direct application to the user's skin.

[0207] Examples of useful dermatological compositions that can be used to deliver the compounds of the present invention or pharmaceutically acceptable salts thereof to the skin are known in the art; see, for example, Jacquet et al. (U.S. Patent 4,608,392; incorporated herein by reference), Geria (U.S. Patent 4,992,478; incorporated herein by reference), Smith et al. (U.S. Patent 4,559,157; ​​incorporated herein by reference), and Wortzman (U.S. Patent 4,820,508; incorporated herein by reference).

[0208] Useful doses of the compounds of the present invention or their pharmaceutically acceptable salts can be determined, at least initially, by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949 (incorporated herein by reference).

[0209] The amount of compound or its pharmaceutically acceptable salt required for use in a procedure varies depending not only on the specific compound or salt selected, but also on the route of administration, the nature of the condition being treated, and the patient's age and condition, and is ultimately at the discretion of the attending physician or clinician.

[0210] However, generally, an appropriate dose is in the range of approximately 0.5 to 100 mg / kg of body weight / day of the recipient, for example, approximately 3 to 90 mg / kg of body weight / day, approximately 6 to 75 mg / kg of body weight / day, approximately 10 to 60 mg / kg of body weight / day, or approximately 15 to 50 mg / kg of body weight / day.

[0211] The compounds of the present invention or pharmaceutically acceptable salts thereof can be conveniently formulated in unit dosage forms; for example, each unit dosage form contains 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of the active compound. In one embodiment, the present invention provides a composition comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, formulated in such unit dosage forms. The desired dose may conveniently be presented as a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more subdoses per day. The subdose itself may be further divided, for example, into several separate, loosely spaced doses.

[0212] The compounds of the present invention or pharmaceutically acceptable salts thereof may also be administered in combination with other therapeutic agents, such as other agents useful for treating or preventing cancer, acute kidney disease, AIDS, or viral infections.

[0213] Other delivery systems include time-release, delayed-release, or sustained-release delivery systems, which are well known in the art. Such systems can avoid repeated administration of the active compound, improving convenience for both the patient and the physician. Many types of release delivery systems are available and known to those skilled in the art. The use of long-term sustained-release implants may be desirable. As used herein, long-term release means a delivery system or implant constructed and configured to deliver therapeutic levels of the active compound for at least 30 days, preferably 60 days.

[0214] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are formulated for intraocular administration, for example, direct injection or insertion within or associated with an intraocular medical device.

[0215] The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated for deposition on medical devices, which may include any of the following: various conventional grafts, stents (including stent grafts), catheters, balloons, baskets, or other devices that can be deployed into or permanently implanted in a body lumen. In particular, it would be desirable to have devices and methods capable of delivering the compounds of the present invention or pharmaceutically acceptable salts thereof to a body area treated by interventional techniques.

[0216] In exemplary embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof may be deposited within a medical device such as a stent and delivered to a treatment site for the treatment of a part of the body.

[0217] Stents have been used as delivery vehicles for therapeutic drugs (i.e., medications). Intravascular stents are generally permanently implanted in coronary or peripheral blood vessels. Stent designs include those in U.S. Patent 4,733,655 (Palmaz), U.S. Patent 4,800,882 (Gianturco), or U.S. Patent 4,886,062 (Wiktor). Such designs include both metal and polymer stents, as well as self-expanding and balloon-expanding stents. Stents may also be used to deliver drugs to a site of contact with the vascular system, as disclosed, for example, in U.S. Patent 5,102,417 (Palmaz), U.S. Patent 5,419,760 (Narciso, Jr.), U.S. Patent 5,429,634 (Narciso, Jr.), and International Patent Application Publications WO91 / 12779 (Medtronic) and WO90 / 13332 (Cedars-Sanai Medical Center).

[0218] The term “deposited” means that the active compound is incorporated into the device by coating, adsorption, placement, or other means by methods known in the art. For example, the active compound may be embedded in a polymer material coating or covering the medical device and released from there (“matrix type”), or surrounded by such a polymer material and released through it (“reservoir type”). In the latter example, the active compound may be captured within the polymer material or bonded to the polymer material using one or more techniques for producing such materials known in the art. In other formulations, the active compound may be bonded to the surface of the medical device, for example by a detachable bond, without requiring a coating, and released over time, or removed by an active mechanical or chemical process. In other formulations, the active compound may be in a permanently immobilized form that presents the active compound at the implantation site.

[0219] In certain embodiments, active compounds may be incorporated into polymer compositions during the formation of biocompatible coatings for medical devices such as stents. Coatings produced from these components are typically homogeneous and useful for coating many devices designed for implantation.

[0220] The polymer can be either biostable or bioabsorbable, depending on the desired release rate or degree of polymer stability. However, unlike biostable polymers, bioabsorbable polymers are often more suitable for this embodiment because they typically remain present for a long time after implantation and do not cause any harmful chronic local reactions. The bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyric acid), poly(hydroxybutyric acid-covaleric acid), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester, and polyphosphoester urea. Examples of suitable bioabsorbable popprimers include, but are not limited to, tans, poly(amino acids), cyanoacrylates, poly(trimethylene carbonates), poly(iminocarbonates), copolymers (ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, and biomolecules (e.g., fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid), polyepsilon caprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable popprimers known in the art.Furthermore, biostable polymers with relatively low chronic tissue reactions, such as polyurethane, silicone, and polyester, can also be used, as well as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halogenated polymers and copolymers (e.g., polyvinyl chloride); polyvinylpyrrolidone; polyvinyl ethers (e.g., polyvinyl methyl ether); polyvinylidene halogens (e.g., polyvinylidene fluoride and polyvinylidene chloride); polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers with each other and with olefins (e.g., ethylene-methyl methacrylate copolymer, acrylonitrile-styrene) Other polymers may also be used if they can be dissolved and cured or polymerized on medical devices, such as copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymers; polyhydroxypropyl-methacrylamide-phenol; polyhydroxyethyl-aspartamido-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides (e.g., nylon 66 and polycaprolactam); alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayons; triacetate rayons; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate-butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose.

[0221] Polymers and semipermeable polymer matrices can be formed into molded articles such as valves, stents, tubes, and prostheses.

[0222] In certain embodiments of the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof is bonded to a polymer or semipermeable polymer matrix formed as a stent or stent graft device.

[0223] Typically, polymers are applied to the surface of implantable devices by spin coating, dipping, or spraying. Further methods known in the art can also be used for this purpose. Spraying methods include traditional methods as well as microdeposition techniques using inkjet-type dispensers. In addition, polymers can be deposited on implantable devices using photopatterning to position the polymer only in specific areas of the device. This coating of the device provides a uniform layer around the device, allowing for improved diffusion of various analytes through the device coating.

[0224] In certain embodiments of the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof is formulated for release from a polymer coating into the environment in which a medical device is placed. Preferably, the active compound is released in a controlled manner over a long period (e.g., several months) using at least one of several known techniques, including a polymer carrier or layer for controlling the elution. Some of these techniques are described in U.S. Patent Application 2004 / 0243225A1, the full disclosure thereof, is incorporated herein in whole.

[0225] Furthermore, as described in U.S. Patent 6,770,729, which is entirely incorporated herein, for example, the reagents and reaction conditions of the polymer composition can be manipulated to control the release of active compounds from the polymer coatings, for example, by adjusting the diffusion coefficients of one or more polymer coatings to control the release of active compounds from the polymer coatings. In a variation of this theme, the diffusion coefficients of one or more polymer coatings can be controlled to regulate the ability of analytes present in the environment in which the medical device is placed (e.g., analytes that promote the decomposition or hydrolysis of a portion of the polymer) to access one or more components in the polymer composition (and, for example, thereby regulating the release of active compounds from the polymer coatings). Yet another embodiment of the present invention includes a device having multiple polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the present invention, the release of active compounds from the polymer coatings can be regulated by the plurality of polymer coatings.

[0226] In yet another embodiment of the present invention, the release of active compounds from a polymer coating is controlled by the presence of one or more endogenous or exogenous compounds, or by adjusting one or more properties of the polymer composition, such as the pH of the polymer composition. For example, a particular polymer composition may be designed to release active compounds in response to a decrease in the pH of the polymer composition. Those skilled in the art will understand that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention included herein, taking into account information known to those skilled in the art, and can be made without departing from the scope of the invention or any of its embodiments. [Examples]

[0227] Although the present invention has been described in detail, the present invention can be understood more clearly by referring to the following examples, which are included for illustrative purposes only and are not intended to limit the present invention.

[0228] The following synthesis scheme represents the synthesis route to the compound of the present invention. Detailed experimental procedures follow the scheme.

[0229] Scheme 1 [ka]

[0230] Scheme 2 [ka]

[0231] Scheme 3 [ka]

[0232] Scheme 4 [ka]

[0233] Scheme 5 [ka]

[0234] Scheme 6 [ka]

[0235] Scheme 7 [ka]

[0236] Scheme 8 [ka]

[0237] Scheme 9 [ka]

[0238] Scheme 10 [ka]

[0239] Scheme 11 [ka]

[0240] Scheme 12 [ka]

[0241] Scheme 13 [ka]

[0242] Scheme 14 [ka]

[0243] Scheme 15 [ka]

[0244] Scheme 16 [ka]

[0245] Scheme 17 [ka]

[0246] Scheme 18 [ka]

[0247] Scheme 19 [ka]

[0248] Scheme 20 [ka]

[0249] Scheme 21 [ka]

[0250] Scheme 22 [ka]

[0251] Scheme 23 [ka]

[0252] Scheme 24 [ka]

[0253] Scheme 25 [ka]

[0254] Scheme 26 [ka]

[0255] Scheme 27 [ka]

[0256] Scheme 28 [ka]

[0257] Scheme 29 [ka]

[0258] Scheme 30 [ka]

[0259] Scheme 31 [ka]

[0260] Scheme 32 [ka]

[0261] Scheme 33 [ka]

[0262] Scheme 34 [ka]

[0263] Scheme 35 [ka]

[0264] Scheme 36 [ka]

[0265] Scheme 37 [ka]

[0266] Scheme 38 [ka]

[0267] Scheme 39 [ka]

[0268] Scheme 40 [ka]

[0269] Scheme 41 [ka]

[0270] Scheme 42 [ka]

[0271] The abbreviations used in the previous scheme or the following examples are listed in the table below. TIFF0007927768000251.tif253170

[0272] Example 1 4-(5-(4'-acetamido-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate [ka]

[0273] Step 1: Methyl 3-(3-bromo-2-methoxyphenyl)-3-oxopropanedithioate To a suspension of NaH (400 mg, 5.00 mmol, 60% suspension in mineral oil) in DMF / hexane (10:1, 11 mL), 1-(3-bromo-2-methoxyphenyl)ethanone (1.14 g, 5.00 mmol) in DMF / hexane (10:1, 1 mL) was added at room temperature under N2. Next, a solution of dimethylcarbonotrithioate (691.3 mg, 5.00 mmol) in DMF / hexane (10:1, 1 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 1N aqueous HCl and extracted by DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 8:1-6:1) to obtain the title compound as a yellow solid (840 mg, yield 53%). LCMS: 318.9(M+H) + .

[0274] Step 2: tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-3-oxopropane oil)piperazine-1-carboxylate A solution of methyl 3-(3-bromo-2-methoxyphenyl)-3-oxopropanedithioate (600 mg, 1.89 mmol) and tert-butylpiperazine-1-carboxylate (386.9 mg, 2.08 mmol) in toluene (25 mL) was stirred overnight at 115°C under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain the title compound as an orange oil (864 mg, 100% yield). LC-MS: 456.9(M+H) + .

[0275] Step 3: tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-3-oxopropanech oil)piperazine-1-carboxylate (775.2 mg, 1.70 mmol) and NH2OH (aqueous solution) (prepared from 6.80 mmol of NH2OH·HCl and 6.80 mmol of KOH in 4 mL of H2O) in EtOH (40 mL) was stirred overnight at 85°C under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was washed with H2O and extracted with EA. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=50:1, PE / EA=6:1) to obtain the title compound as a yellow solid (230.1 mg, yield 28%). LC-MS: 437.9(M+H) + .

[0276] Step 4: tert-butyl 4-(5-(4'-acetamido-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate (251.8 mg, 0.59 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (616.2 mg, 2.36 mmol), K3PO4 (375.7 mg, 1.77 mmol), and Pd(dppf)Cl2.DCM (87.8 mg, 0.2 mmol) in dioxane / water (4:1, 15 mL) was stirred under a nitrogen atmosphere at 110 °C in a microwave for 20 hours. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with H2O and extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA=10:1 to PE / EA=2:1) ​​to obtain the title compound as a pale yellow solid (160.0 mg, yield 53%). 1 H NMR (400 MHz, DMSO-d6): 10.05 (s, 1H), 7.76-7.74 (m, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.47-7.45 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 6.75 (s, 1H), 3.46-3.44 (m, 4H), 3.32 (s, 3H), 3.27-3.25 (m, 4H), 2.08 (s, 3H), 1.42 (s, 9H). LCMS: 493.2 (M + H) + .

[0277] Example 2 N-(2'-Methoxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0278] A solution of tert-butyl 4-(5-(4'-acetamido-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate (15 mg, 0.03 mmol) in dioxane (1 mL) and HCl (4 M, 3 mL) in dioxane was stirred at room temperature for 3 hours. After the reaction was completed by LC-MS, the reaction mixture was concentrated. The residue was dissolved in H2O and lyophilized to obtain the HCl salt of the title compound as a yellow solid (8.5 mg, yield 72%). 1 H NMR (400 MHz, DMSO-d6): 10.12 (s, 1H), 9.16 (br s, 1H), 7.77-7.75 (m, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.52-7.46 (m, 3H), 7.34 (t, J = 8.0 Hz, 1H), 6.82 (s, 1H), 3.55-3.53 (m, 4H), 3.32 (s, 3H), 3.23-3.21 (m, 4H), 2.08 (s, 3H). LCMS: 393.2 (M + H) + .

[0279] Example 3 N-(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0280] To a solution of tert-butyl 4-(5-(4'-acetamido-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (1 mL), BBr3 (8 mL, 17% in DCM) was added. The reaction mixture was stirred overnight under a nitrogen atmosphere at 0°C to 5°C. After the reaction was completed by LC-MS, the reaction mixture was quenched with MeOH at 0°C. The mixture was concentrated, and the residue was purified by preparative HPLC (NH4HCO3) to obtain the crude compound. The crude compound was dissolved in HCl / dioxane (4 M, 4 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was then concentrated and lyophilized to obtain the HCl salt of the title compound as an orange solid (21.3 mg, yield 29%). 1 H NMR (400 MHz, DMSO-d6): 0.09 (s, 1H), 9.28 (br s, 1H), 9.20-9.16 (m, 2H), 7.68-7.64 (m, 3H), 7.43 (t, J = 8.4 Hz, 2H), 7.31 (d, J = 6.8 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.54-3.42 (m, 4H), 3.30-3.21 (m, 4H), 2.07 (s, 3H). LCMS: 379.2 (M + H) + .

[0281] Example 5 N-(3'-(3-((2S,6R)-2,6-dimethylmorpholino)isoxazol-5-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0282] The title compound was prepared using methyl 3-(3-bromo-2-methoxyphenyl)-3-oxopropanedithioate and (2R,6S)-2,6-dimethylmorpholine according to the procedure described in Example 1, and the title compound was obtained as a white solid (48.3 mg, yield 20%). 1H NMR (400 MHz, DMSO-d6): 10.07 (s, 1H), 7.76-7.74 (m, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.47-7.45 (m, 1H), 7.33 LCMS: 422.2 (M+H) + .

[0283] Example 6 N-(2'-hydroxy-3'-(3-(4-methylpiperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0284] A mixture of N-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide hydrobromide (68.0 mg, 0.18 mmol), HCHO (5.4 mg, 0.18 mmol), and NaBH3CN (169.6 mg, 2.70 mmol) in MeOH (4 mL) was stirred at room temperature (rt) for 0.5 hours. After the reaction was completed by LC-MS, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted by DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to obtain the TFA salt of the title compound as a yellow solid (29.6 mg, yield 39%). This TFA salt was converted to an HCl salt using HCl in dioxane to obtain a yellow solid. 1H NMR (400 MHz, DMSO-d6): 10.04 (s, 1H), 9.18 (s, 1H), 7.68-7.65 (m, 3H), 7.44 (d, J = 8.8 Hz, 2H), 7.32-7.30 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.76 (s, 1H), 3.88-3.61 (m, 4H), 3.35-3.18 (m, 4H), 2.86 (s, 3H), 2.07 (s, 3H). LCMS: 393.0 (M + H) + .

[0285] Example 7 N-(2'-Methoxy-3'-(3-(4-methylpiperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0286] The title compound was prepared using N-(2'-methoxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide, HCHO, and NaBH3CN according to the procedure described for Example 6, and the title compound was obtained as a white solid (3.7 mg, 5% yield). 1 H NMR (400 MHz, DMSO-d6): 10.08 (s, 1H), 9.86 (br s, 1H), 7.77-7.75 (m, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.52-7.47 (m, 3H), 7.35 (t, J = LCMS: 407.0 (M + H) + .

[0287] Example 8 N-(2'-hydroxy-3'-(5-(piperazine-1-yl)isothiazol-3-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0288] Step 1: tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)isothiazol-5-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-3-oxopropanech oil)piperazine-1-carboxylate (1.82 g, 4.00 mmol) in AcOH (10 mL), NH4OAc (1.54 g, 20.00 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. LC-MS showed that tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-3-oxopropanech oil)piperazine-1-carboxylate remained. Additional NH4OAC (3.08 g, 40.0 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. After the reaction was complete as determined by LC-MS, the reaction mixture was concentrated, the residue was dissolved in H2O (40 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by silica gel chromatography using a 6:1 mixture of petroleum ether / ethyl acetate as the eluent to obtain the title compound as a yellow solid (500 mg, yield 28%). LCMS: 456.1(M+H) + .

[0289] Step 2: 2-Bromo-6-(5-(piperazine-1-yl)isothiazol-3-yl)phenol To a solution of tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)isothiazol-5-yl)piperazine-1-carboxylate (400 mg, 0.88 mmol) in DCM (3 mL), BBr3 (5 mL, 17% in DCM) was added at 0°C. The solution was stirred under a nitrogen atmosphere at room temperature for 3 hours. After the reaction was completed by LC-MS, the reaction mixture was quenched with MeOH (5 mL) at 0°C. The mixture was concentrated. The residue was adjusted to pH 8-10 with saturated NaHCO3 and extracted with DCM (3 × 20 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a yellow solid (270 mg, 90% yield). LC-MS: 340.0 (M + H) + .

[0290] Step 3: N-(2'-hydroxy-3'-(5-(piperazine-1-yl)isothiazol-3-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using 2-bromo-6-(5-(piperazin-1-yl)isothiazol-3-yl)phenol, N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide, K3PO4, and Pd(dppf)Cl2.DCM according to the procedure described in Step 4 of Example 1 to obtain the crude product, which was purified by preparative HPLC using acetonitrile in water in the presence of HCl to obtain the title compound as an HCl salt. 1 H NMR (400 MHz, DMSO-d6) (HCl salt): 12.42 (br s, 1H), 10.02 (s, 1H), 9.28 (br s, 2H), 7.84-7.81 (m, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.51 (d, J LCMS: 395.2 (M+H) + .

[0291] Example 9 N-(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)-N-methylacetamide [ka]

[0292] The title compound was prepared using 2-bromo-6-(3-(piperazin-1-yl)isoxazole-5-yl)phenol, N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide, K3PO4, and Pd(dppf)Cl2.DCM according to the procedure described in Step 4 of Example 1, to obtain the crude product, which was purified by preparative HPLC using acetonitrile in water in the presence of TFA to obtain the title compound as the TFA salt. 1 H NMR (400 MHz, DMSO-d6): 9.35 (s, 1H), 8.88 (br s, 2H), 7.71-7.69 (m, 1H), 7.58-7.56 (m, 2H), 7.42-7.26 (m, 3H), 7.13-7.09 (m, 1H), 6.76 (s, 1H), 3.50-3.47 (m, 8H), 3.24-3.20 (m, 3H), 1.86 (s, 3H). LCMS: 393.2 (M + H) + .

[0293] Example 11 N,N'-(2'-hydroxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0294] The title compound was prepared using 2,6-dibromophenol and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described in Step 4 of Example 1, to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6): 9.99 (s, 2H), 8.16 (s, 1H), 7.62 (d, J = 8.8 Hz, 4H), 7.45 (d, J = 8.4 Hz, 4H), 7.15 (d, J = 8.0 Hz, 2H), 6.99-6.96 (m, 1H), 2.06 (s, 6H). LCMS: 361.1 (M + H) + .

[0295] Example 12 N-(2'-hydroxy-[1,1':3',1''-terphenyl]-4-yl)acetamide [ka]

[0296] Step 1: N-(3'-bromo-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide A solution of 2-bromo-6-iodophenol (150.0 mg, 0.50 mmol), N-(4-(4,4,5,5-tetramethyl)1,3,2-dioxaborolan-2-yl)phenyl)acetamide (130.6 mg, 0.50 mmol), K3PO4 (318.3 mg, 1.50 mmol), and Pd(dppf)Cl2.DCM (73.2 mg, 0.10 mmol) in water (9:1, 5 mL) was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. After the reaction was completed by LC-MS, the reaction mixture was used directly in the next step without further purification. LC-MS: 306.0 (M+H) + .

[0297] Step 2: N-(2'-hydroxy-[1,1':3',1''-terphenyl]-4-yl)acetamide To a solution of N-(3'-bromo-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide (152.5 mg, 0.50 mmol) in dioxane:water (9:1, 5 mL), phenylboronic acid (122.0 mg, 1.00 mmol), K3PO4 (318.3 mg, 1.50 mmol), and Pd(dppf)Cl2.DCM (73.2 mg, 0.10 mmol) were added. The reaction mixture was stirred overnight at 100°C under a nitrogen atmosphere. The starting materials did not react completely. Therefore, 0.20 equivalents of Pd(dppf)2Cl2 and 3.00 equivalents of phenylboronic acid were added to the reaction mixture. The reaction mixture was heated at 110°C for 10 hours. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography (PE to PE / EA = 1:1) to obtain the title compound as a white solid (22.1 mg, yield 15%). 1 H NMR (400 MHz, DMSO-d6): 10.00 (s, 1H), 8.21 (s, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.53 (d, J = 6.8 Hz, 2H), 7.47-7.41 (m, 4H), 7 .34 (d, J = 6.4 Hz, 1H), 7.18 (s, 2H), 7.00 (t, J = 6.8 Hz, 1H), 2.06 (s, 3H). LCMS: 304.2 (M + H) + .

[0298] [Table 1-1] [Table 1-2]

[0299] Example 18 N-(3'-(4-(4-fluorophenyl)-1H-imidazole-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0300] A mixture of N-(3'-bromo-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide (305 mg, 1.00 mmol), 4-(4-fluorophenyl)-1H-imidazole (324 mg, 2.20 mmol), L-proline (207 mg, 1.80 mmol), Cu2O (129 mg, 0.9 mmol), and K2CO3 (276 mg, 2.0 mmol) in dioxane (10 mL) was heated at 105°C for 4 days under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate / dichloromethane (1:1:1) followed by dichloromethane / methanol (20:1) to obtain the crude product, which was further purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as an off-white solid (30.3 mg, yield 7%). 1 H NMR (400 MHz, DMSO-d6): 10.02 (s, 1H), 9.03 (s, 1H), 7.96-7.86 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.35-7.30 (m, 2H), 7.24-7.20 (m, 2H), 7.10-7.06 (m, 1H), 2.07 (s, 3H). LCMS: 388.1 (M + H) + .

[0301] Example 19 N-(3-ethoxy-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0302] Step 1: 2-Bromo-6-(3-(piperazin-1-yl)isoxazole-5-yl)phenol To a solution of tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate (50 mg, 0.11 mmol) in DCM (0.5 mL), BBr3 (1 mL, 17% in DCM) was added at 0°C. The solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed by LC-MS, the mixture was quenched with MeOH (1 mL) at 0°C. The mixture was concentrated to obtain the title compound (37 mg, crude product, 100% yield) as a gray solid. LC-MS: 324.0 (M+H) + .

[0303] Step 2: 4-Bromo-2-ethoxy-1-nitrobenzene To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2.0 g, 9.09 mmol) in EtOH (20 mL), EtONa (1.85 g, 27.27 mmol) was added. The solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed by LC-MS, the reaction mixture was concentrated. The residue was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (2.28 g, crude, yield 100%) as a yellow solid. LC-MS: 245.7 (M + H) + .

[0304] Step 3: 4-bromo-2-ethoxyaniline To a mixture of 4-bromo-2-ethoxy-1-nitrobenzene (2.28 g, 9.27 mmol) in MeOH (45 mL) and H2O (15 mL), Fe (5.19 g, 92.7 mmol) and NH4Cl (4.96 g, 92.7 mmol) were added. The reaction mixture was stirred at 50°C for 3 hours. After the reaction was complete by LC-MS, the reaction mixture was filtered and concentrated. The residue was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (1.75 g, crude, yield 88%) as a brown oil. LC-MS: 216.0 (M + H) + .

[0305] Step 4: N-(4-bromo-2-ethoxyphenyl)acetamide To a solution of 4-bromo-2-ethoxyaniline (750 mg, 3.47 mmol) in THF (7 mL), acetic anhydride (0.5 mL) was added dropwise. The solution was stirred under a nitrogen atmosphere at room temperature for 2 hours. After the reaction was confirmed by LC-MS, the reaction mixture was concentrated to obtain the title compound as a gray solid (880 mg, 98% yield). LC-MS: 258.0 (M + H) + .

[0306] Step 5: N-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide A solution of N-(4-bromo-2-ethoxyphenyl)acetamide (516 mg, 2.00 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (610 mg, 2.40 mmol), KOAc (589 mg, 6.01 mmol), and Pd(dppf)Cl2.DCM (73 mg, 0.20 mmol) in dioxane (10 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the residue, which was purified by silica gel chromatography using petroleum ether and ethyl acetate (5:1) as the eluent to obtain the title compound as a yellow solid (550 mg, 90% yield). LC-MS: 306.2(M+H) + .

[0307] Step 6: N-(3-ethoxy-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetic acid A mixture of 2-bromo-6-(3-(piperazin-1-yl)isoxazole-5-yl)phenol (37 mg, 0.11 mmol), N-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (139 mg, 0.45 mmol), K3PO4 (94 mg, 0.45 mmol), and Pd(dppf)Cl2.DCM (16 mg, 0.022 mmol) in dioxane:water (8:1, 6 mL) was stirred at 110 °C for 2 hours under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified by silica gel chromatography using DCM / MeOH (10:1) to obtain the crude product. The crude product was purified by preparative HPLC using acetonitrile in water in the presence of TFA to obtain the title compound as a pale yellow oil (9.3 mg, yield 16%). 1 H NMR (400 MHz, DMSO-d6) (TFA salt): (s, 1H), 9.04 (s, 1H), 8.82 (br s, 2H), 8.03 (d, J = 8.4 Hz, 1H), 7.68-7.66 (m, 1H), 7.36-7.34 (m, 1H), 7.13 (s, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.03-7.01 (m, 1H), 6.74 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 3.50-3.47 (m, 4H), 3.26-3.20 (m, 4H), 2.13 (s, 3H), 1.40 (t, J = 6.8 Hz, 3H). LCMS: 423.2 (M + H) + .

[0308] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0309] Example 29 5-Acetyl-8-(2-hydroxy-3-(3-(piperazine-1-yl)isoxazole-5-yl)phenyl)-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-one 2,2,2-trifluoroacetate [ka]

[0310] Step 1: 5-Acetyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-one A solution of 5-acetyl-8-bromo-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-one (500 mg, 1.77 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (675.5 mg, 2.66 mmol), KOAc (521 mg, 5.3 mmol), and PdCl2 (124 mg, 0.17 mmol) in dioxane (12 mL) was stirred at 85°C for 16 hours under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled, diluted with EA, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (10:1) as the eluent to obtain the title compound as a white solid (525.6 mg, 90% yield). LCMS:331.1(M+H) + .

[0311] Step 2: tert-butyl4-(5-(3-(1-acetyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl)-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate (224.7 mg, 0.437 mmol, 85% purity), 5-acetyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-one (360.2 mg, 1.09 mmol), K3PO4 (278.8 mg, 1.31 mmol), and Pd(dppf)Cl2 (79.8 mg, 0.109 mmol) in dioxane:water (10:1, 9.9 mL) was stirred at 105°C for 2.5 hours under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography using petroleum ether, ethyl acetate, and dichloromethane (1:1:1) as eluents to obtain the title compound as a yellow solid (190 mg, 77% yield). LCMS: 562.3(M+H) + .

[0312] Step 3: 5-Acetyl-8-(2-hydroxy-3-(3-(piperazine-1-yl)isoxazole-5-yl)phenyl)-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-one 2,2,2-trifluoroacetate To a solution of tert-butyl 4-(5-(3-(1-acetyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl)-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate (110 mg, 0.196 mmol) in DCM (0.5 mL), BBr3 (4.5 mL, 17% in DCM) was added dropwise at 0°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 8 hours. The reaction mixture was quenched with H2O (5 mL), and Na2CO3 (530 mg, 5.00 mmol) was added at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was extracted with DCM:MeOH (5 mL × 10, 10:1). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by preparative HPLC using acetonitrile in water in the presence of TFA to obtain the title compound as a white solid (17.1 mg, yield 16%). 1 H NMR (400 MHz, DMSO-d6): 9.85 (s, 1H), 9.43 (s, 1H), 8.83 (br s, 2H), 7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.45 (J = 8.4 Hz, 1H), 7.36 (dd, J = 9.2, 1.2 Hz, 1H), 7.32-7.30 (m, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 4.75-4.67 (m, 1H), 3.50-3.47 (m, 4H), 3.24 (s, 5H), 2.72 (br s, 1H), 2.33 (s, 1H), 1.78 (s, 3H). LCMS: 448.2 (M + H) + .

[0313] [Table 3-1] [Table 3-2]

[0314] N,N'-(3,3''-difluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0315] A mixture of N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (200 mg, 0.72 mmol), 2,6-dibromophenol (91 mg, 0.36 mmol), K3PO4 (458 mg, 2.16 mmol), and Pd(dppf)Cl2 (112 mg, 0.14 mmol) in dioxane:water (10:3, 13 mL) was stirred at 100 °C for 4 hours under N2. After the reaction was shown by LC-MS, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (28.0 mg, yield 10%). 1 H NMR (400 MHz, DMSO-d6): 9.77 (s, 2H), 8.53 (s, 1H), 7.93 (t, J = 8.4 Hz, 2H), 7.43 (d, J = 2.0, 2H), 7.40 (d, J = 2.0 Hz, 2H), 7.30 (dd, J = 8.4, 2.0 Hz, 2H), 7.02 (t, J = 7.6, 1H), 2.11 (s, 6H). LCMS: 397.1 (M + H) + .

[0316] Example 34 N-(3-fluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide trifluoroacetate [ka]

[0317] The title compound was prepared using N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-fluorophenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate, followed by BBr3, according to the procedure described in Example 1, to obtain the TFA salt of the title compound (yield 21%). 1 H NMR (400 MHz, DMSO-d6): 9.81 (s, 1H), 9.36 (s, 1H), 8.84 (br s, 2H), 7.98 (t, J = 8.4, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.29 (m, 2H), 7.29-7.27 (m, 1H), 7.11-7.08 (m, 1H), 6.76 (s, 1H), 3.56-3.47 (m, 4H), 3.42-3.24 (m, 4H), 2.11 (s, 3H). LCMS: 397.2 (M + H) + .

[0318] Example 35 N-(3-fluoro-2'-hydroxy-3'-(1-phenyl-1H-pyrazole-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0319] Step 1: N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide A mixture of N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (200 mg, 0.72 mmol), 2,6-dibromophenol (910 mg, 3.6 mmol), K3PO4 (458 mg, 2.16 mmol), and Pd(dppf)Cl2 (112 mg, 0.14 mmol) in dioxane:water (10:3, 13 mL) was stirred at 100°C for 4 hours under N2. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (186.0 mg, yield 80%). LC-MS: 324.0(M+H) + .

[0320] Step 2: N-(3-fluoro-2'-hydroxy-3'-(1-phenyl-1H-pyrazole-4-yl)-[1,1'-biphenyl]-4-yl)acetamide A solution of N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide (100 mg, 0.32 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (121 mg, 0.45 mmol), K3PO4 (191 mg, 0.9 mmol), and Pd(dppf)Cl2 (43.8 mg, 0.06 mmol) in dioxane:water (10:3, 13 mL) was stirred at 110 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled and concentrated. The residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (4.7 mg, yield 4%). 1H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 8.84 (s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 7.95 (t, J = 8.4 Hz, 1H), 7.90-7.87 (m, 2H), 7.62-7.60 (m, 1H), 7.52 (t, J = 7.6, 2H), 7.42 (d, J = 1.6 Hz, 1H), 7.40-7.30 (m, 2H), 7.17 (dd, J = 7.2, 1.6 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 2.12 (s, 3H). LCMS: 388.1 (M + H) + .

[0321] [Table 4-1] [Table 4-2]

[0322] Example 40 N,N'-(5,5'-(2-hydroxy-1,3-phenylene)bis(pyridine-5,2-diyl))diacetamide [ka]

[0323] A mixture of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)acetamide (230.6 mg, 0.88 mmol), 2,6-dibromophenol (100 mg, 0.40 mmol), K3PO4 (339.2 mg, 1.60 mmol), and Pd(dppf)Cl2 (58.5 mg, 0.08 mmol) in dioxane:water (5:3, 8 mL) was stirred at 110 °C for 4 hours under N2. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (5.7 mg, yield 4%). 1 H NMR (400 MHz, DMSO-d6): 10.54 (s, 2H), 8.64 (s, 1H), 8.46 (d, J = 1.6 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 7.92 (dd, J = 8.4, 2.0 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 7.2 Hz, 1H), 2.12 (s, 6H). LCMS: 363.1 (M + H) + .

[0324] Example 41 1-(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)imidazolidinedione-2-one 2,2,2-trifluoroacetate [ka]

[0325] The title compound was prepared using 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazolidined-2-one [prepared from 4-1-(bromophenyl)imidazolidined-2-one and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate, followed by BBr3, according to the procedure described in Example 29, to obtain the TFA salt of the title compound (yield 29%). 1 H NMR (400 MHz, DMSO-d6): 9.18 (s, 1H), 8.78 (br s, 2H), 7.65 (d, J = 8.8 Hz, 3H), 7.45 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 7.6, 1.2 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 3.89 (t, J = 8.4 Hz, 2H), 3.48-3.42 (m, 6H), 3.25-3.23 (m, 4H). LCMS: 406.2 (M + H) + .

[0326] Example 42 N,N'-(3-fluoro-2'-hydroxy-3''-methoxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0327] Step 1: N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide A mixture of N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (5.0 g, 17.9 mmol), 2,6-dibromophenol (22.6 g, 89.6 mmol), K3PO4 (22.8 g, 107.4 mmol), and Pd(dppf)Cl2 (2.6 g, 3.58 mmol) in water (10:3, 260 mL) was stirred at 100 °C for 4 hours under N2. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (2:1) as the eluent to obtain the title compound as a green solid (2.3 g, yield 40%). LC-MS: 324.0 (M+H) + .

[0328] Step 2: N,N'-(3-fluoro-2'-hydroxy-3''-methoxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide A solution of N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide (150 mg, 0.46 mmol), N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (204 mg, 0.7 mmol), K3PO4 (293 mg, 1.38 mmol), and Pd(dppf)2Cl2 (65.8 mg, 0.09 mmol) in dioxane:water (10:3, 13 mL) was stirred at 110 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC, and the title compound was obtained as a white solid using acetonitrile in water in the presence of NaHCO3 (38.2 mg, yield 20%). 1H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 9.19 (s, 1H), 8.39 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.42 (dd, J = 12.0, 1.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.25-7.23 (m, 2H), 7.18 (d, J = 2.0 Hz, 1H), 7.06-6.99 (m, 2H), 3.87 (s, 3H), 2.11 (s, 6H). LCMS: 409.1 (M+H) + .

[0329] Example 43 1-(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one 2,2,2-trifluoroacetate [ka]

[0330] The title compound was prepared using 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one [prepared from 1-(4-bromophenyl)pyrrolidine-2-one and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate, followed by BBr3, according to the procedure described for Example 29, to obtain the TFA salt of the title compound (yield 5%). 1H NMR (400 MHz, DMSO-d6): 9.24 (br s, 1H), 8.83 (br s, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.68-7.66 (m, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 7.6, 1.6 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.75 (s, 1H), 3.88 (t, J = 7.2 Hz, 2H), 3.49-3.47 (m, 4H), 3.25-3.22 (m, 4H), 2.55-2.50 (m, 2H), 2.13-2.06 (m, 2H). LCMS: 405.2 (M + H) + .

[0331] Example 44 N-(3-cyclopropoxy-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0332] The title compound was prepared using N-(2-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-cyclopropoxyphenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and 2-bromo-6-(3-(piperazine-1-yl)isoxazole-5-yl)phenol according to the procedure described in Example 19, and the TFA salt of the title compound was obtained as a white solid (9.3 mg, yield 8%). 1H NMR (400 MHz, DMSO-d6): 9.25 (s, 1H), 9.04 (s, 1H), 8.80 (br s, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 2.0 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 7.6, 2.0 Hz, 1H), 7.11-7.04 (m, 2H), 6.74 (s, 1H), 3.94-3.91 (m, 1H), 3.49-3.47 (m, 4H), 3.27-3.23 (m, 4H), 2.10 (s, 3H),0.81-0.78 (m, 4H).LCMS: 435.2 (M + H) + .

[0333] Example 45 N,N'-(3-cyclobutoxy-3''-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0334] The title compound was prepared using N-(2-cyclobutoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-cyclobutoxyphenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as a white solid (10.4 mg, yield 5%). 1H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 9.03 (s, 1H), 8.40 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.40 (dd, J = 12.4, 1.6 Hz, 1H), 7.32-7.29 (m, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.05-6.99 (m, 3H), 4.79-4.76 (m, 1H), 2.47-2.41 (m, 2H), 2.20-2.15 (m, 2H), 2.13 (s, 6H), 1.80-1.78 (m, 1H), 1.68-1.63 (m, 1H). LCMS: 449.2 (M + H) + .

[0335] Example 46 N,N'-(3-chloro-3''-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0336] The title compound was prepared using N-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-chlorophenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as a white solid (yield 34%). 1H NMR (400 MHz, DMSO-d6): 9.77 (s, 1H), 9.55 (s, 1H), 8.58 (s, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.47-7.40 (m, 2H), 7.32-7.30 (m, 1H), 7.27-7.24 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 2.11 (m, 6H). LCMS: 413.1 (M + H) +1 .

[0337] Example 47 N-(3'-(1-acetylindoline-5-yl)-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0338] The title compound was prepared using 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-yl)ethanone and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as a white solid (48.3 mg, yield 26%). 1 H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 8.32 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.40 (s, 1H), 7.32-7.29 (m, 2H), 7.22-7.18 (m, 2H), 6.99 (t, J = 7.6 Hz, 1H), 4.13 (t, J = 7.6 Hz, 2H), 3.18 (t, J = 8.0 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H).LCMS: 405.1 (M + H) +.

[0339] Example 48 2,2-Difluoro-N-(2'-Hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0340] The title compound was prepared using tert-butyl 4-(5-(4'-amino-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate and 2,2-difluoroacetic anhydride according to the procedure described for Example 39, and the TFA salt of the title compound was obtained as a white solid (23.5 mg, yield 43%). 1 H NMR (400 MHz, DMSO-d6):10.87 (s, 1H), 9.26 (s, 1H), 8.87 (br s, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.35-7.32 (m, 1H), 7.13-7.08 (m, 2H), 6.75 (s, 1H), 6.42 (t, J = 53.6 Hz, 1H), 3.50-3.47 (m, 4H), 3.25-3.24 (m, 4H). LCMS: 415.2 (M + H) + .

[0341] Example 49 N,N'-(3-cyano-3''-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0342] The title compound was prepared using N-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as a white solid (77.5 mg, yield 62%). 1 H NMR (400 MHz, DMSO-d6): 10.20 (s, 1H), 9.78 (s, 1H), 8.66 (s, 1H), 7.93 (t, J = 2.0 Hz, 2H), 7.83-7.81 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.44-7.41 (m, 1H), 7.33-7.27 (m, 3H), 7.05 (t, J = 8.0 Hz, 1H), 2.13 (s, 3H), 2.11 (s, 3H). LCMS: 404.1 (M + H) + .

[0343] Example 50 N,N'-(3-fluoro-2'-hydroxy-3''-methyl-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0344] The title compound was prepared using N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as an off-white solid (33.5 mg, yield 28%). 1H NMR (400 MHz, DMSO-d6): 9.76 (s, 1H), 9.31 (s, 1H), 8.37 (s, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.48-7.37 (m, 3H), 7.30 (d, J = 9.2 Hz, 2H), 7.23-7.19 (m, 2H), 7.00 (t, J = 7.6 Hz, 1H), 2.25 (s, 3H), 2.11 (s, 3H), 2.08 (s, 3H). LCMS: 393.2 (M + H) + .

[0345] [Table 5-1] [Table 5-2]

[0346] Example 57 N-(3'-(3-(4-acetylpiperazine-1-yl)isoxazole-5-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0347] To a solution of N-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide (40 mg, 0.1 mmol) in DCM (15 mL), AC2O (1.1 mL) and TEA (0.3 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. Saturated aqueous NaHCO3 (10 mL) and MeOH (10 mL) were added, and the mixture was then heated to 60°C for 16 hours. After the reaction was complete by LC-MS, the solvent was removed from the reaction mixture under reduced pressure to obtain the residue, to which water (10 mL) was added and extracted with EA (6 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (5.0 mg, yield 12%). 1 H NMR (400 MHz, DMSO-d6): 10.02 (s, 1H), 9.11 (br s, 1H), 7.67-7.63 (m, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.31-7.29 (m, 1H), 7.17 (t, J = LCMS: 421.2 (M + H) + .

[0348] Example 58 N-(2'-hydroxy-3'-(3-(4-(phenylsulfonyl)piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0349] To a solution of N-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide (70 mg, 0.1 mmol) in DCM (2 mL), benzenesulfonyl chloride (17.7 mg, 0.1 mmol) and TEA (30.3 mg, 0.30 mmol) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. Saturated aqueous NaHCO3 (10 mL) and MeOH (10 mL) were added, and the mixture was then heated to 60 °C for 16 hours. After the reaction was complete by LC-MS, the solvent was removed from the mixture under reduced pressure to obtain the residue, to which water (10 mL) was added and extracted with EA (6 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (10.9 mg, yield 21%). 1 H NMR (400 MHz, DMSO-d6): 10.01 (s, 1H), 9.09 (br s, 1H), 7.78-7.73 (m, 3H), 7.69-7.60 (m, 5H), 7.41 (d, J = 8.8 Hz, 2H), 7.29-7.27 (m, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.63 (s, 1H), 3.37-3.31 (m, 4H), 3.03-3.01 (m, 4H), 2.08 (s, 3H).LCMS: 519.2 (M + H) + .

[0350] [Table 6]

[0351] Example 62 8-(2-hydroxy-3-(3-(piperazin-1-yl)isoxazole-5-yl)phenyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one [ka]

[0352] Step 1: 3-(5-bromo-2-nitrophenoxy)propane-1-ol To a solution of propane-1,3-diol (13.8 g, 181.8 mmol) in DMF (100 mL), NaH (2.2 g, 54.6 mmol, 60%) was added all at once. The reaction mixture was stirred at 0°C for 30 minutes. 4-bromo-2-fluoro-1-nitrobenzene (10.0 g, 45.5 mmol) was added. The reaction mixture was then stirred at 0°C for 2 hours. The reaction mixture was quenched with 1N HCl. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, to which water (20 mL) was added and extracted with EA (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (11.0 g, yield 88%) as a yellow oil, which was used in the next step without further purification.

[0353] Step 2: 3-(5-bromo-2-nitrophenoxy)propanoic acid To a solution of 3-(5-bromo-2-nitrophenoxy)propan-1-ol (2.0 g, 43.6 mmol) in acetone (200 mL) at 0°C, a chromic acid solution prepared from CrO3 (8.7 g, 87.2 mmol), water (30 mL), and concentrated H2SO4 (13.6 g, 139.5 mmol) at 0°C was slowly added. The reaction mixture was then stirred at 0°C for 2 hours. Ice-cold water was added to the reaction mixture, and it was extracted with EA (15 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (2:1) as eluents to obtain the title compound as a yellow solid (8.0 g, yield 63%). LCMS: 290.2(M+H) + .

[0354] Step 3: 3-(2-amino-5-bromophenoxy)propanoic acid To a solution of 3-(5-bromo-2-nitrophenoxy)propanoic acid (8.0 g, 27.7 mmol) in MeOH (100 mL) and H2O (20 mL), NH4Cl (11.8 g, 221.6 mmol) and Fe powder (7.7 g, 138.4 mmol) were added. The reaction mixture was stirred at 75°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to obtain the residue. This residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (1:10) as the eluent to obtain the title compound as a brown solid (1.5 g, yield 21%). LCMS: 260.0(M+H) + .

[0355] Step 4: 8-bromo-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one To a solution of 3-(2-amino-5-bromophenoxy)propanoic acid (1.5 g, 5.8 mmol) in DMF (20 mL), HATU (4.4 g, 11.6 mmol) and DIPEA (2.2 g, 17.4 mmol) were added. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to obtain the residue. Water was added to the residue, and it was extracted with EA. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (1:1) as eluents to obtain the title compound as a white solid (600 mg, yield 43%). LCMS: 242.0(M+H) + .

[0356] Step 5: 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one The title compound was prepared using 8-bromo-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described for Example 29, and the title compound was obtained (100% yield). LCMS: 290.1(M+H)+ .

[0357] Step 6: 8-(2-hydroxy-3-(3-(piperazin-1-yl)isoxazole-5-yl)phenyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one 2,2,2-trifluoroacetate The title compound was prepared using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one and 2-bromo-6-(3-(piperazine-1-yl)isoxazole-5-yl)phenol according to the procedure described for Example 29 to obtain the TFA salt of the title compound (yield 1%). 1 H NMR (400 MHz, DMSO-d6): 9.86 (s, 1H), 9.25 (s, 1H), 8.81 (br s, 1H), 7.68-7.65 (m, 1H), 7.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.15 (s, 3H), 7.08 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 4.40 (t, J = 6.0 Hz, 2H), 3.49-3.47 (m, 4H), 3.36-3.24 (m, 4H), 2.75 (t, J = 5.6 Hz, 2H). LCMS: 407.2 (M+H) + .

[0358] Example 63 N-(3-fluoro-2'-hydroxy-3'-(pyridine-3-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0359] The title compound was prepared using pyridine-3-ylboronic acid and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as a white solid (55 mg, yield 55%). 1 H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.53 (t, J = 2.0 Hz, 1H), 7.95-7.92 (m, 2H), 7.48-7.40 (m, 2H), 7.33-7.27 (m, 3H), 7.07 (t, J = 7.6 Hz, 1H), 2.11 (s, 3H). LCMS: 323.1 (M + H) + .

[0360] Example 64 N-(3-cyano-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0361] The title compound was prepared using N-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide and 2-bromo-6-(3-(piperazine-1-yl)isoxazole-5-yl)phenol according to the procedure described in Example 19, and the TFA salt of the title compound was obtained as a white solid (9.4 mg, yield 7%). 1H NMR (400 MHz, DMSO-d6): 10.25 (s, 1H), 9.49 (s, 1H), 8.80 (br s, 2H), 7.90 (d, J = 2.4 Hz, 1H), 7.80-7.77 (m, 1H), 7.73-7.67 (m, 2H), 7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 3.50-3.48 (m, 4H), 3.34-3.24 (m, 4H), 2.14 (s, 3H). LCMS: 404.2 (M + H) + .

[0362] Example 65 1-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one 2,2,2-trifluoroacetate [ka]

[0363] Step 1: tert-butyl 4-(5-(2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate (100 mg, 0.229 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazolidinedione-2-one (173 mg, 0.573 mmol), K3PO4 (41 mg, 0.057 mmol), and Pd(dppf)Cl2 (145 mg, 0.687 mmol) in dioxane:water (10:1, 4.95 mL) was stirred overnight at 105°C. After the reaction was completed by LC-MS and TLC, the reaction mixture was diluted with DCM, filtered to obtain the residue, and purified by silica gel chromatography using petroleum ether and ethyl acetate (1:1) as the eluent to obtain the title compound as a white solid (70.0 mg, yield 57%). LC-MS: 534.2(M+H) + .

[0364] Step 2: 1-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one 2,2,2-trifluoroacetate To a solution of tert-butyl 4-(5-(2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate) (65 mg, 0.12 mmol) in DCM (4 mL), BBr3 in DCM (2 mL) was added. The reaction mixture was stirred overnight at 0°C under a nitrogen atmosphere. After the reaction was shown by LC-MS, the reaction product was quenched with MeOH and NaHCO3 was added until no more bubbles were observed. The resulting mixture was filtered. The solution was concentrated and purified by preparative HPLC using acetonitrile in water in the presence of TFA to obtain the TFA salt of the title compound as a white solid (1.42 mg, yield 2%). 1H NMR (400 MHz, DMSO-d6): 9.16 (br s, 1H), 8.80 (br s, 2H), 7.65 (br s, 3H), 7.46 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.85-3.82 (m, 2H), 3.48-3.35 (m, 6H), 3.33-3.24 (m, 4H), 2.79 (s, 3H). LCMS: 420.2 (M + H) + .

[0365] Example 66 2-Fluoro-N-(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0366] In the presence of HATU and TEA, the title compound was prepared using tert-butyl 4-(5-(4'-amino-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate and 2-fluoroacetic acid according to the procedure described in Example 39, and the TFA salt of the title compound was obtained as a white solid (23.5 mg, yield 43%). 1H NMR (400 MHz, DMSO-d6): 10.20 (s, 1H), 9.22 (s, 1H), 8.80 (br s, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 5.08 (s, 1H), 4.96 (s, 1H), 3.50-3.47 (m, 4H), 3.30-3.20 (m, 4H).LCMS: 397.2 (M + H) + .

[0367] Example 67 N-(3-fluoro-2'-hydroxy-3'-(pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0368] The title compound was prepared using pyridine-4-ylboronic acid and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained as a white solid (24% yield). 1 H NMR (400 MHz, DMSO-d6): 9.79 (s, 1H), 8.74 (s, 1H), 8.61 (d, J = 6.4 Hz, 2H), 7.94 (t, J = 8.4 Hz, 1H), 7.56 (d, J = 6.0 Hz, 2H), 7.42 (dd, J = 12.0, 1.6 Hz, 1H), 7.32-7.30 (m, 2H), 7.08 (t, J = 7.6 Hz, 1H), 2.11 (s, 3H). LCMS: 323.1 (M + H) + .

[0369] Example 68 N-(2'-hydroxy-3-phenoxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0370] The title compound was prepared using N-(2-phenoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (prepared from N-(4-bromo-2-phenoxyphenyl)acetamide and [4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and tert-butyl4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate), followed by reaction with BBr3 in DCM to obtain the title compound as a white solid (yield 58%) according to the procedure described in Example 19. 1 H NMR (400 MHz, DMSO-d6): 9.55 (s, 1H), 9.28 (s, 1H), 8.77 (br s, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.0, 2.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.30-7.24 (m, 2H), 7.14-7.10 (m, 1H), 7.10-7.02 (m, 4H), 6.71 (s, 1H), 3.48-3.46 (m, 4H), 3.30-3.20 (m, 4H), 2.05 (s, 3H). LCMS: 471.2 (M + H) + .

[0371] [Table 7-1] [Table 7-2] [Table 7-3]

[0372] Example 76 N-(5-(2-hydroxy-3-(3-(piperazine-1-yl)isoxazole-5-yl)phenyl)pyridine-2-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0373] The title compound was prepared using N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)acetamide and tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate according to the procedure described in Example 1 to obtain the TFA salt of the title compound (20% yield). 1 H NMR (400 MHz, DMSO-d6): 10.60 (s, 1H), 9.41 (br s, 1H), 8.85 (s, 2H), 8.42 (d, J = 1.6 Hz, 1H), 8.16-8.14 (m, 1H), 7.91-7.89 (m, 1H), 7.72-7.70 (m, 1H), 7.39-7.37 (m, 1H), 7.14-7.10 (m, 1H),6.77 (s, 1H), 3.50-3.48 (m, 3H), 3.24 (s, 4H), 2.13 (s, 3H). LCMS: 380.2 (M+H) + . [Table 8-1] [Table 8-2]

[0374] Example 84 N-(3,5'-difluoro-2'-hydroxy-3'-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0375] The title compound was prepared using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)piperidine and N-(3'-bromo-3,5'-difluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide, following the procedure described for Example 35, to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6): 9.75 (s, 1H), 8.31 (s, 2H), 7.95-7.88 (m, 2H), 7.36-7.30 (m, 3H), 6.93-6.90 (m, 1H), 4.12-4.08 (m, 1H), 2.87-2.84 (m, 2H), 2.20 (s, 3H), 2.10-1.93 (m, 9H). LCMS: 427.2 (M + H) + .

[0376] Example 85 N-(3-fluoro-2'-hydroxy-3'-(2-phenyloxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0377] Step 1: 5-(3-bromo-2-methoxyphenyl)-2-phenyloxazole To a solution of 1-(3-bromo-2-methoxyphenyl)ethanone (1.6 g, 7.0 mmol) and 2-amino-2-phenylacetic acid (1.27 g, 8.4 mmol) in DMSO (40 mL), p-ABS (606 mg, 3.5 mmol) and I2 (3.55 g, 14.0 mmol) were added. The reaction mixture was stirred at 100 °C for 5 hours under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the reaction mixture was quenched with saturated Na2S2O3 and extracted with EA (80 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (6:1) as eluents to obtain the title compound as a yellow solid (1.8 g, yield 78%). LC-MS: 330.0 (M+H) + .

[0378] Step 2: N-(3-fluoro-2'-methoxy-3'-(2-phenyloxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using 5-(3-bromo-2-methoxyphenyl)-2-phenyloxazole and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 54, yielding the title compound (83% yield). LCMS: 403.1(M+H) + .

[0379] Step 3: N-(3-fluoro-2'-hydroxy-3'-(2-phenyloxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using N-(3-fluoro-2'-methoxy-3'-(2-phenyloxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 65, and the title compound was obtained (yield 53.6%). 1H NMR (400 MHz, DMSO-d6): 9.82 (s, 1H), 8.35 (s, 1H), 8.13 (d, J = 1.6 Hz, 2H), 8.11 (t, J = 0.8 Hz, 1H), 7.99-7.85 (m, 1H), 7.72 (s, 1H), 7.60-7.55 (m, 3H), 7.42-7.27 (m, 3H), 7.13 (t, J = 7.2 Hz, 1H), 2.13 (s, 3H). LCMS: 389.1 (M + H) + .

[0380] Example 86 N-(3,5-difluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0381] The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-hydroxyphenyl)isoxazol-3-yl)piperazine-1-carboxylate and N-{2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described in Example 1, and the title compound was obtained (yield 50%). 1 H NMR (400 MHz, DMSO-d6): 9.75 (s, 1H), 9.56 (s, 1H), 8.84 (s, 2H), 7.72 (d, J = 6.8 Hz, 1H), 7.42-7.40 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 3.50-3.47 (m, 4H), 3.24 (s, 4H), 2.09 (s, 3H). LCMS: 415.1 (M + H) + .

[0382] Example 87 N,N'-(3-fluoro-2'-hydroxy-3''-isopropoxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0383] The title compound was prepared using N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide and N-(2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 42, and the title compound was obtained (yield 29%). 1 H NMR (400 MHz, DMSO-d6): 9.76 (s, 1H), 8.88 (s, 1H), 8.38 (s, 1H), 8.01-7.89 (m, 2H), 7.42 (d, J = 12.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.24-7.18 (m, 3H), 7.04-6.98 (m, 2H), 4.66-4.60 (m, 1H), 2.12-2.07 (m, 6H), 1.33 (d, J = 6.0 Hz, 6H). LCMS: 437.2 (M + H) + .

[0384] Example 88 N,N'-(3-ethyl-3''-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4,4''-diyl)diacetamide [ka]

[0385] The title compound was prepared using N-(2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-ethylphenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 42, and the title compound was obtained (yield 44%). 1 H NMR (400 MHz, DMSO-d6): 9.76 (s, 1H), 9.30 (s, 1H), 8.40 (s, 1H), 7.94-7.90 (m, 1H), 7.42-7.38 (m, 3H), 7.33-7.30 (m, 2H), 7.23-7.21 (m, 2H), 7.03-6.99 (m, 1H), 2.66-2.61 (m, 2H), 2.11-2.07 (m, 6H), 1.23-1.14 (m, 3H). LCMS: 407.1 (M + H) + .

[0386] Example 89 N-(3-(cyclopentyloxy)-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0387] The title compound was prepared using N-(2-cyclopentyloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from 4-bromo-2-fluoro-1-nitrobenzene, cyclopentanol, and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and 2-bromo-6-(3-(piperazine-1-yl)isoxazole-5-yl)phenol according to the procedure described for Example 19, and the title compound was obtained as a white solid (20% yield). 1 H NMR (400 MHz, DMSO-d6): 9.23 (s, 1H), 8.87-8.85 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 7.68-7.66 (m, 1H), 7.35-7.33 (m, 1H), 7.11-7.06 (m, 2H), 7.02-7.00 (m, 1H), 6.73 (s, 1H), 4.89-4.86 (m, 1H), 3.50-3.47 (m, 4H), 3.24 (s, 4H), 2.12 (s, 3H), 1.92-1.85 (m, 4H), 1.79-1.75 (m, 2H), 1.61-1.56 (m, 2H). LCMS: 463.2 (M + H) + .

[0388] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0389] Example 100 N-(3-cyclobutoxy-5-fluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0390] The title compound was prepared using N-(2-cyclobutoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-cyclobutoxy-6-fluorophenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)] and 2-bromo-6-(3-(piperazine-1-yl)isoxazole-5-yl)phenol according to the procedure described in Example 19, and the title compound was obtained as a pale yellow solid (yield 12%). 1 H NMR (400 MHz, DMSO-d6- TFA salt): 9.46 (s, 1H), 9.27 (s, 1H), 8.80 (s, 2H), 7.70 (dd, J = 7.6, 1.6 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 1H), 7.12-7.08 (m, 1H), 6.96-6.93 (m, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 4.80-4.76 (m, 1H), 3.50-3.47 (m, 4H), 3.24 (s, 4H), 2.45-2.38 (m, 2H), 2.10-2.05 (m, 5H), 1.79-1.76 (m, 1H), 1.63-1.61 (m, 1H). LCMS: 467.2 (M + H) + .

[0391] [Table 10-1] [Table 10-2]

[0392] Example 105 N-(3'-(3-(4-benzoylpiperazine-1-yl)isoxazole-5-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0393] Step 1: N-(2'-Methoxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide A solution of tert-butyl 4-(5-(4'-acetamido-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate (100 mg, 0.200 mmol) in 4N HCl in dioxane (6 mL) was stirred at room temperature under N2 for 3 hours. After the reaction mixture was completed by LC-MS, the reaction mixture was concentrated under reduced pressure to obtain the title compound (78 mg, 100%) as a white solid. LC-MS: 393.2(M+H) + .

[0394] Step 2: N-(3'-(3-(4-benzoylpiperazine-1-yl)isoxazole-5-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide To a solution of N-(2'-methoxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide (78 mg, 0.20 mmol) in DCM (2 mL), TEA (64 mg, 0.60 mmol) and benzoyl chloride (28 mg, 0.20 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under N2 for 16 hours. After the reaction mixture was completed by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (1:1) as eluents to obtain the title compound (40 mg, 40%) as a white solid. LC-MS: 497.3(M+H)+ .

[0395] Step 3: N-(3'-(3-(4-benzoylpiperazine-1-yl)isoxazole-5-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using N-(3'-(3-(4-benzoylpiperazin-1-yl)isoxazole-5-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide and BBr3 according to the procedure described in Example 1 to obtain the title compound (yield 13%). 1 H NMR (400 MHz, DMSO-d6): 10.01 (s, 1H), 9.13 (s, 1H), 7.66-7.64 (m, 3H), 7.48-7.43 (m, 7H), 7.30-7.28 (m, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.70 (s, 1H), 3.74-3.47 (m, 4H), 3.31-3.29 (m, 4H), 2.07 (s, 3H). LCMS: 483.2 (M + H) + .

[0396] [Table 11-1] [Table 11-2] [Table 11-3]

[0397] Example 112 N-(3-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)oxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0398] Step 1: 5-(3-bromo-2-methoxyphenyl)oxazole: To a solution of 3-bromo-2-methoxybenzaldehyde (785 mg, 4.65 mmol) in MeOH (20 mL), K2CO3 (834 mg, 6.04 mmol) and Tosmic (785 mg, 5.12 mmol) were added. The reaction mixture was stirred under N2 at room temperature for 16 hours. After the reaction was complete by LC-MS, the reaction mixture was concentrated. The residue was diluted with H2O (50 mL) and extracted with EA (40 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the residue, which was used as a pale yellow solid in the next step without further purification (800 mg, yield 68%). LC-MS: 254.0 (M + H) + .

[0399] Step 2: 5-(3-bromo-2-methoxyphenyl)-2-chlorooxazole To a solution of 5-(3-bromo-2-methoxyphenyl)oxazole (800 mg, 3.15 mmol) in THF (20 mL), LiHMDS (3.46 mL, 3.46 mmol) was added dropwise at -78°C. The mixture was stirred for 30 minutes, after which C2Cl6 (1.49 g, 6.30 mmol) was added at -78°C. The reaction mixture was then stirred under N2 at room temperature for 16 hours. After the reaction was complete by LC-MS, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA (40 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as eluents to obtain the title compound (590 mg, 65%) as a white solid. LC-MS: 288.0 (M+H) + .

[0400] Step 3: tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)oxazol-2-yl)piperazine-1-carboxylate: DIPEA (358 mg, 2.78 mmol) was added to a solution of 5-(3-bromo-2-methoxyphenyl)-2-chloroxazole (400 mg, 1.39 mmol) and tert-butylpiperazine-1-carboxylate (284 mg, 1.53 mmol) in dioxane (12 mL). The reaction mixture was stirred at 100 °C for 4 hours under N2. After the reaction was completed by LC-MS, the reaction mixture was concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as the eluents to obtain the title compound (430 mg, 71%) as a pale yellow solid. LC-MS: 438.1(M+H) + .

[0401] Step 4: tert-butyl 4-(5-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)oxazol-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)oxazol-2-yl)piperazine-1-carboxylate and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 1, and the title compound was obtained (yield 98%). LCMS: 511.3(M+H) + .

[0402] Step 5: N-(3-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)oxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetamide: The title compound was prepared using tert-butyl 4-(5-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)oxazole-2-yl)piperazine-1-carboxylate according to the procedure described for Example 1, and the title compound was obtained (yield 15%). 1¹H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 12.0 Hz, 1H), 7.28-7.25 (m, 2H), 7.09 (d, J = 6.4 Hz, 1H), 6.97 (d, J = 6.4 Hz, 1H), 3.40 (t, J = 4.4 Hz, 4H), 2.78 (t, J = 4.8 Hz, 4H), 2.11 (s, 3H). NH and OH protons were not observed. 19 F NMR (376 MHz, DMSO-d6): δ -125.33. LCMS: 397.2 (M + H) + .

[0403] Example 113 1-(3-fluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one [ka]

[0404] The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one according to the procedure described for Example 43, and the title compound was obtained (yield 22%). 11H NMR (400 MHz, DMSO-d6): δ 7.66 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.39-7.34 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.67 (s, 1H), 3.79 (t, J = 7.2 Hz, 2H), 3.16 (t, J = 4.8 Hz, 4H), 2.80 (t, J = 4.8 Hz, 4H), 2.47-2.43 (m, 2H), 2.16-2.12 (m, 2H). NH and OH protons were not observed. 19 F NMR (376MHz, DMSO-d6): δ -119.94. LCMS: 423.2 (M + H) + .

[0405] Example 114 N-(3''-cyclobutoxy-3-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4-yl)acetamide [ka]

[0406] The title compound was prepared using N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide] and 2-(3-cyclobutoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [prepared from 1-bromo-3-cyclobutoxybenzene and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)] according to the procedure described for Example 42, and the title compound was obtained (yield 2%). 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.38 (s, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 12.4 Hz, 1.2 Hz, 1H), 7.34-7.30 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 7.02-6.99 (m, 2H), 6.81 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 4.75-4.68 (m, 1H), 2.46-2.39 (m, 2H), 2.10 (s, 3H), 2.08–2.01 (m, 2H), 1.79–1.75 (m, 1H), 1.68–1.61 (m, 1H). No NH or OH protons were observed. LCMS: 392.2 (M + H) + .

[0407] Example 115 N-(3''-(cyclopentyloxy)-3-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4-yl)acetamide [ka]

[0408] The title compound was prepared using N-(3'-bromo-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide and 1-bromo-3-(cyclopentyloxy)benzene, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) [prepared from 1-bromo-3-cyclopentyloxybenzene and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)] according to the procedure described for Example 42 to obtain the title compound. 1H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 8.36 (s, 1H), 7.91 (t, J = 8.8 Hz, 1H), 7.41 (dd, J = 12.0 Hz, 1.2 Hz, 1H), 7.34-7.30 (m, 2H), 7.22 (t, J = 7.2 Hz, 2H), 7.05-6.99 (m, 3H), 6.87 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 4.86-4.83 (m, 1H), 2.10 (s, 3H), 1.96-1.87 (m, 2H), 1.75-1.66 (m, 4H), 1.63-1.56 (m, 2H). LCMS: 406.2 (M + H) + .

[0409] Example 116 N-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)propionamide 2,2,2-trifluoroacetate [ka]

[0410] The title compound was prepared using tert-butyl 4-(5-(4'-amino-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate and propionic acid according to the procedure described for Example 42, and the TFA salt of the title compound was obtained as a white solid (yield 32%). 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.16 (s, 1H), 8.81 (br s, 2H), 7.69-7.64 (m, 3H), 7.42 (d, J = 8.4 Hz, 2H), 7.31 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.09-7.05 (m, 1H), 6.73 (s, 1H), 3.50-3.46 (m, 4H), 3.25-3.21 (m, 4H), 2.34 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). LCMS: 393.3 (M + H) + .

[0411] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4]

[0412] Example 126 N-(3-chloro-5-fluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0413] The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazol-3-yl)piperazine-1-carboxylate and N-(2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [prepared from N-(4-bromo-2-chloro-6-fluorophenyl)acetamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolan)], followed by BBr3, according to the procedure described in Example 1, to obtain the title compound (23% yield). 1 H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 9.60 (s, 1H), 8.79 (br s, 2H), 7.73 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.50 (s, 1H), 7.43-7.40 (m, 2H), 7.12 (t, J = 7.6 Hz, 1H), 6.78 (s, 1H), 3.51-3.46 (m, 4H), 3.24 (s, 4H), 2.09 (s, 3H). LCMS: 431.1 (M + H) + .

[0414] [Table 13-1] [Table 13-2] [Table 13-3]

[0415] Example 134 N-(5'-Fluoro-2'-Hydroxy-3'-(1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0416] The title compound was prepared using N-(3'-bromo-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)piperidine according to the procedure described for Example 84, and the title compound was obtained (yield 13%). 1 H NMR (400 MHz, DMSO-d6): 10.01 (s, 1H), 8.33 (s, 1H), 8.23 ​​(s, 1H), 7.97 (s, 1H), 7.65-7.63 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 10.0, 3.2 Hz, 1H), 6.87 (dd, J = 9.6, 3.2 Hz, 1H), 4.15-4.11 (m, 1H), 2.87-2.84 (m, 2H), 2.21 (s, 3H), 2.07-1.94 (m, 9H). LCMS: 409.2 (M+H) + .

[0417] Example 135 N-(3-cyclopropoxy-5-fluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0418] NHC-Pd(II) (84 mg, 0.07 mmol) was added to a solution of 2-bromo-6-(3-(piperazin-1-yl)isoxazole-5-yl)phenol hydrobromide (100 mg, 0.249 mmol), N-(2-cyclopropoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (250 mg, 0.747 mmol), and K2CO3 (206 mg, 1.49 mmol) in a sealed tube. The reaction mixture was stirred at 120°C for 4 hours under a nitrogen atmosphere. After the reaction was complete by LC-MS, the reaction mixture was cooled, diluted with DCM / MeOH (20:1, 5 mL), and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography using dichloromethane and methanol (15:1) as eluents, and then further purified by preparative HPLC using acetonitrile in water in the presence of TFA to obtain the title compound as a white solid (7.1 mg, yield 4%). 1 ¹H NMR (400 MHz, DMSO-d6): 9.49 (s, 1H), 9.24 (s, 1H), 8.82 (s, 2H), 7.73-7.70 (m, 1H), 7.42-7.39 (m, 1H), 7.27 (s, 1H), 7.13-6.97 (m, 2H), 6.75 (s, 1H), 3.95-3.92 (m, 1H), 3.68-3.65 (m, 3H), 3.24 (s, 4H), 2.02 (s, 3H), 0.80-0.77 (m, 2H), 0.72-0.68 (m, 2H). No NH or OH protons were observed. LCMS: 453.2 (M + H) + .

[0419] [Table 14-1] [Table 14-2]

[0420] Example 140 1-(3,5-difluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one [ka]

[0421] Step 1: 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one The title compound was prepared using 1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described in Example 133, yielding the title compound (100% yield). LCMS: 324.2(M+H) + .

[0422] Step 2: tert-butyl 4-(5-(3',5'-difluoro-2-methoxy-4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate The title compound was prepared using 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one and tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate, following the procedure described for Example 1, to obtain the title compound (yield 44%). LCMS: 555.0(M+H) + .

[0423] Step 3: 1-(3,5-difluoro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one The title compound was prepared using tert-butyl 4-(5-(3',5'-difluoro-2-methoxy-4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl)-3-yl)isoxazole-3-yl)piperazine-1-carboxylate according to the procedure described in Example 1, and the title compound was obtained (13% yield). 1 H NMR (400 MHz, DMSO-d6): 7.68 (d, J = 8.0 Hz, 1H), 7.43-7.37 (m, 3H), 7.02-6.98 (m, 1H), 6.71 (s, 1H), 3.73-3.69 (m, 2H), 3.20 (s, 4H), 2.85 (s, 4H), 2.50-2.45 (m, 2H), 2.22-2.18 (m, 2H). LCMS: 441.2 (M + H) + .

[0424] Example 141 Methyl(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)carbamate 2,2,2-trifluoroacetate [ka]

[0425] The title compound was prepared using tert-butyl 4-(5-(4'-amino-2-methoxy-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate and methyl chloroformate, following the procedure described for Example 39, to obtain the title compound (44% yield). 11H NMR (400 MHz, DMSO-d6): 9.77 (s, 1H), 9.18 (s, 1H), 8.80 (br s, 2H), 7.67-7.64 (m, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.32-7.29 (m, 1H), 7.09-7.05 (m, 1H), 6.74 (s, 1H), 3.69 (s, 3H), 3.49-3.47 (m, 3H), 3.24 (s, 4H). No NH or OH protons were observed. LCMS: 395.2 (M + H) + .

[0426] Example 143 N-(2'-hydroxy-3'-(3-(4-(methylsulfonyl)piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0427] Step 1: N-(2'-Methoxy-3'-(3-(4-(methylsulfonyl)piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide To a solution of N-(2'-methoxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide (78 mg, 0.2 mmol) in DCM (2 mL), MsCl (23 mg, 0.20 mmol) and TEA (60 mg, 0.60 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After the reaction was completed by LC-MS, the reaction mixture was concentrated, water was added, and it was extracted with EA. The combined organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound. LC-MS: 471.2(M+H) + .

[0428] Step 2: N-(2'-hydroxy-3'-(3-(4-(methylsulfonyl)piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using N-(2'-methoxy-3'-(3-(4-(methylsulfonyl)piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide and BBr3 according to the procedure described for Example 1 to obtain the title compound (16% yield). 1 H NMR (400 MHz, DMSO-d6): 10.02 (s, 1H), 9.13 (s, 1H), 7.67-7.64 (m, 3H), 7.44 (d, J = 8.8 Hz, 2H), 7.31-7.29 (m, 1H), 7.09-7.05 (m, 1H), 6.72 (s, 1H), 3.40-3.31 (m, 4H), 3.25-3.22 (m, 4H), 2.92 (s, 3H), 2.07 (s, 3H). LCMS: 457.2 (M + H) + .

[0429] [Table 15-1] [Table 15-2]

[0430] Example 148 N-(3-fluoro-2'-hydroxy-3'-(5-(piperazin-1-yl)-4H-1,2,4-triazole-3-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0431] Step 1: 3-Bromo-2-methoxybenzoyl chloride A solution of 3-bromo-2-methoxybenzoic acid (900 mg, 3.90 mmol) and DMF (2 drops) in DCM (10 mL) was mixed with a solution of oxalyl dichloride (742 mg, 580 mmol) in DCM (5 mL). The solution was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was concentrated to obtain the title compound as a yellow oil (967 mg, 99% yield).

[0432] Step 2: 3-Bromo-2-methoxybenzoate hydrazide A solution of hydrazine hydrate (975 mg, 19.5 mmol) in a mixture of DCM (5 mL) and THF (7 mL) was mixed with a solution of 3-bromo-2-methoxybenzoyl chloride (976 mg, 3.90 mmol) in DCM (2 mL). The solution was stirred under a nitrogen atmosphere at room temperature for 16 hours. After the reaction was completed by LC-MS, the reaction mixture was quenched with MeOH (20 mL) and concentrated. The residue was purified by silica gel chromatography using dichloromethane and methanol (10:1) as eluents to obtain the title compound as a white solid (300 mg, yield 32%). LC-MS: 245.0 (M+H) + .

[0433] Step 3: tert-butyl 4-(imino(methylthio)methyl)piperazine-1-carboxylate hydroiodide A solution of tert-butyl 4-carbamimidylpiperazine-1-carboxylate (900 mg, 3.70 mmol) and iodomethane (782 mg, 3.50 mmol) in MeOH (30 mL) was stirred at 50°C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled and concentrated to obtain the title compound as a yellow solid (1.40 g, 100% yield).

[0434] Step 4: tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)-4H-1,2,4-triazole-3-yl)piperazine-1-carboxylate A suspension of tert-butyl 4-(imino(methylthio)methyl)piperazine-1-carboxylate hydroiodide (1.40 g, 3.60 mmol) and 3-bromo-2-methoxybenzoate hydrazide (883 mg, 3.60 mmol) in pyridine (10 mL) was stirred overnight at 100°C under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (2:1) as eluents to obtain the title compound as a yellow solid (300 mg, yield 19%). LC-MS: 438.1(M+H) + .

[0435] Step 5: tert-butyl 4-(5-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-4H-1,2,4-triazole-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)-4H-1,2,4-triazole-3-yl)piperazine-1-carboxylate and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described in Example 1, yielding the title compound (72% yield). LCMS: 511.2(M+H) + .

[0436] Step 6: N-(3-fluoro-2'-hydroxy-3'-(5-(piperazin-1-yl)-4H-1,2,4-triazole-3-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 4-(5-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-4H-1,2,4-triazole-3-yl)piperazine-1-carboxylate according to the procedure described for Example 1, and the title compound was obtained (yield 31%). 1¹H NMR (400 MHz, DMSO-d6): 12.07 (br s, 1H), 9.77 (s, 1H), 7.94-7.87 (m, 2H), 7.52-7.48 (m, 1H), 7.39-7.36 (m, 2H), 7.01-6.97 (m, 1H), 3.33-3.31 (m, 4H), 2.81-2.79 (m, 4H), 2.11 (s, 3H). No two NH or OH protons were observed. LCMS: 397.2 (M + H) + .

[0437] Example 149 1-(2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)-3-methylurea [ka]

[0438] Step 1: tert-butyl 4-(5-(2-methoxy-4'-(3-methylureido)-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate and 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea according to the procedure described in Example 1, and the title compound was obtained (yield 71%). LCMS: 508.2(M+H) + .

[0439] Step 2: 1-(2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)-3-methylurea The title compound was prepared using tert-butyl 4-(5-(2-methoxy-4'-(3-methylureido)-[1,1'-biphenyl]-3-yl)isoxazole-3-yl)piperazine-1-carboxylate and BBr3 according to the procedure described in Examples 1-3 to obtain the title compound (12% yield). 1 ¹H NMR (400 MHz, DMSO-d6): 8.61 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.49-7.46 (m, 2H), 7.38-7.36 (m, 2H), 7.28-7.26 (m, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.04 (s, 1H), 3.16 (s, 4H), 2.81 (s, 4H), 2.66 (d, J = 4.0 Hz, 3H). No two NH or OH protons were observed. LCMS: 394.2 (M + H) + .

[0440] Example 150 N-(3-fluoro-2'-hydroxy-3'-(3-(4-methylpiperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0441] To a solution of N-(3-fluoro-2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide hydrobromide) (70 mg, 0.15 mmol) in MeOH (3 mL), NaBH3(CN) (37.7 mg, 0.600 mmol) was added, followed by HCHO (9.5 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was completed by LC-MS, the reaction mixture was quenched with aqueous NH4Cl solution and concentrated. The residue was purified by preparative HPLC to obtain the title compound as a white solid (13 mg, yield 31%). 1H NMR (400 MHz, DMSO-d6): 9.80 (s, 1H), 9.27 (br s, 1H), 7.99-7.95 (m, 1H), 7.66 (dd, J = 7.6, 1.2 Hz, 1H), 7.40-7.27 (m, 3H), 7.10-7.06 (m, 1H), 6.67 (s, 1H), 3.26-3.23 (m, 4H), 2.44-2.41 (m, 4H), 2.22 (s, 3H), 2.12 (s, 3H). LCMS: 411.2 (M + H) + .

[0442] Example 151 N-(3'-(3-(4-ethylpiperazine-1-yl)isoxazole-5-yl)-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0443] The title compound was prepared using N-(3-fluoro-2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide hydrobromide and acetaldehyde, following the procedure described for Example 150, to obtain the title compound (yield 37%). 1 H NMR (400 MHz, DMSO-d6): 9.80 (s, 1H), 9.27 (br s, 1H), 7.99-7.95 (m, 1H), 7.67 (dd, J = 7.6, 1.6 Hz, 1H), 7.40-7.27 (m, 3H), 7.10-7.06 (m, 1H), 6.67 (s, 1H), 3.26-3.24 (m, 4H), 2.51-2.49 (m, 4H), 2.41-2.32 (m, 2H), 2.12 (s, 3H), 1.05-1.01 (m, 3H). LCMS: 425.2 (M+H) + .

[0444] Example 152 N-(3-fluoro-2'-hydroxy-3'-(3-(4-isopropylpiperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0445] The title compound was prepared using N-(3-fluoro-2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide hydrobromide and propan-2-one according to the procedure described for Example 150, and the title compound was obtained (16% yield). 1 H NMR (400 MHz, DMSO-d6): 9.81 (s, 1H), 9.60 (br s, 1H), 9.36 (s, 1H), 8.00-7.96 (m, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.28 (m, 3H), 7.12-7.08 (m, 1H), 6.79 (s, 1H), 3.94-3.91 (m, 2H), 3.56-3.50 (m, 3H), 3.22-3.15 (m, 4H), 2.12 (s, 3H), 1.30-1.28 (m, 6H).LCMS: 439.2 (M+H) + .

[0446] Example 153 N-(3-fluoro-2'-hydroxy-3'-(3-(4-(oxetan-3-yl)piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0447] The title compound was prepared using N-(3-fluoro-2'-hydroxy-3'-(3-(piperazin-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide hydrobromide and oxetane-3-one according to the procedure described for Example 150, and the title compound was obtained (yield 29%). 1 H NMR (400 MHz, DMSO-d6): 9.80 (s, 1H), 9.26 (br s, 1H), 7.97-7.95 (m, 1H), 7.67 (dd, J = 8.0, 2.0 Hz, 1H), 7.40-7.27 (m, 3H), 7.08 (t, J = 8.0 Hz, 1H), 6.69 (s, 1H), 4.58-4.54 (m, 2H), 4.48-4.45 (m, 2H), 3.47-3.44 (m, 1H), 3.29-3.26 (m, 4H), 2.51-2.49 (m, 4H), 2.11 (s, 3H). LCMS: 453.2 (M+ H) + .

[0448] Example 154 N-(3,5-dichloro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0449] The title compound was prepared using tert-butyl 4-(5-(3-bromo-2-methoxyphenyl)isoxazole-3-yl)piperazine-1-carboxylate and N-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide, followed by BBr3, according to the procedure described for Example 1, to obtain the title compound (yield 34%). 1¹H NMR (400 MHz, DMSO-d6): 9.85 (s, 1H), 7.66 (s, 3H), 7.38-7.36 (m, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.72 (s, 1H), 3.20-3.17 (m, 4H), 2.85-2.82 (m, 4H), 2.08 (s, 3H). No two NH or OH protons were observed. LCMS: 447.1 (M + H) + .

[0450] [Table 16-1] [Table 16-2]

[0451] Example 159 N-(3''-(4-aminopiperidine-1-yl)-3-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4-yl)acetamide 2,2,2-trifluoroacetate [ka]

[0452] Step 1: tert-butyl(1-(3-bromophenyl)piperidine-4-yl)carbamate To a solution of 1-bromo-3-iodobenzene (0.60 mL, 5.0 mmol) and tert-butylpiperidine-4-ylcarbamate (1.0 g, 5.0 mmol) in toluene (10 mL), t-BuONa (1.37 g, 14.0 mmol), BINAP (156 mg, 0.250 mmol), and Pd2(dba)3 (229 mg, 0.250 mmol) were added. The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as the eluent to obtain the title compound as a yellow solid (800 mg, yield 45%). LC-MS: 355.1(M+H) + .

[0453] Step 2: tert-butyl(1-(4''-acetamido-3''-fluoro-2'-methoxy-[1,1':3',1''-terphenyl]-3-yl)piperidine-4-yl)carbamate The title compound was prepared using tert-butyl(1-(3-bromophenyl)piperidine-4-yl)carbamate and N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 1, yielding the title compound (72% yield). LCMS: 534.2(M+H) + .

[0454] Step 3: tert-butyl N-(3''-(4-aminopiperidine-1-yl)-3-fluoro-2'-hydroxy-[1,1':3',1''-terphenyl]-4-yl)acetamido 2,2,2-trifluoroacetate The title compound was prepared using tert-butyl(1-(4''-acetamido-3''-fluoro-2'-methoxy-[1,1':3,1''-terphenyl]-3-yl)piperidine-4-yl)carbamate and BBr3, following the procedure described for Example 3, to obtain the title compound (yield 55%). 11H NMR (400 MHz, DMSO-d6): 9.87 (s, 1H), 8.36 (br s, 1H), 7.92-7.90 (m, 4H), 7.41 (dd, J = 12.4, 2.0 Hz, 1H), 7.32-7.19 (m, 3H), 7.11 (s, 1H), 7.03-6.96 (m, 3H), 3.81-3.77 (m, 2H), 3.24-3.20 (m, 1H), 2.87-2.81 (m, 2H), 2.11 (s, 3H), 1.97-1.95 (m, 2H), 1.68-1.58 (m, 2H). No NH or OH protons were observed. LCMS: 420.2 (M + H) + .

[0455] Example 160 N-(3-fluoro-2'-hydroxy-3'-(1-methyl-5-(piperazin-1-yl)-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0456] Step 1: tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-1H-pyrazole-5-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-3-oxopropanech oil)piperazine-1-carboxylate (1.43 g, 3.14 mmol) in EtOH (5 mL), NH2NH2·H2O (5 mL) was added. The reaction mixture was stirred under a nitrogen atmosphere at 84 °C for 2 hours. After the reaction was completed by LC-MS, the reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (PE / EA = 1:1) to obtain the title compound as a yellow solid (820 mg, yield 60%). LC-MS: 437.1(M+H) + .

[0457] Step 2: tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-yl)piperazine-1-carboxylate A suspension of NaH (36 mg, 0.92 mmol, 60 wt% of mineral oil) in THF (8 mL) was mixed with a solution of tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-1H-pyrazole-5-yl)piperazine-1-carboxylate (400 mg, 0.920 mmol) in THF (7 mL) at 0°C. After stirring at 0°C for 30 minutes, CH3I (260 mg, 1.84 mmol) was added. The reaction mixture was stirred at room temperature for a further 4 hours under an N2 atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with EA (15 mL x 3). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 2:1) to obtain the title compound as a colorless oil (250 mg, yield 60%). LCMS: 451.1 (M+H) + .

[0458] Step 3: 2-Bromo-6-(1-methyl-5-(piperazin-1-yl)-1H-pyrazole-3-yl)phenol The title compound was prepared using tert-butyl 4-(3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-yl)piperazine-1-carboxylate and BBr3, following the procedure described in Example 3, to obtain the title compound (crude product). LCMS: 337.0(M+H) + .

[0459] Step 4: N-(3-fluoro-2'-hydroxy-3'-(1-methyl-5-(piperazin-1-yl)-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using 2-bromo-6-(1-methyl-5-(piperazin-1-yl)-1H-pyrazole-3-yl)phenol and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described in Example 1, and the title compound was obtained (yield 11%). 1 1H NMR (400 MHz, DMSO-d6): 11.50 (br s, 1H), 9.78 (s, 1H), 7.94-7.90 (m, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.52-7.48 (m, 1H), 7.39-7.26 (m, 2H), 6.99-6.95 (m, 1H), 6.51 (s, 1H), 3.73 (s, 3H), 3.05-2.88 (m, 8H), 2.12 (s, 3H). No NH or OH protons were observed. LCMS: 410.3 (M + H) + .

[0460] Example 162 N-(3-fluoro-2'-hydroxy-3'-(5-(piperazin-1-yl)-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)acetamide ditrifluoroacetate [ka]

[0461] The title compound was prepared using 2-bromo-6-(5-(piperazin-1-yl)-1H-pyrazole-3-yl)phenol and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 160, and the title compound was obtained (yield 2%). 1H NMR (400 MHz, DMSO-d6+D2O): 7.86 (s, 1H), 7.66-7.63 (m, 1H), 7.47 (dd, J = 12.4, 1.6 Hz, 1H), 7.39-7.28 (m, 2H), 7.05-7.01 (m, 1H), 6.32 (s, 1H), 3.44-3.41 (m, 4H), 3.29-3.26 (m, 4H), 2.12 (s, 3H). LCMS: 396.2 (M + H) + .

[0462] Example 163 N-(3-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0463] Step 1: tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide and tert-butyl 4-(4-bromopyridine-2-yl)piperazine-1-carboxylate according to the procedure described for Example 159, yielding the title compound (26% yield). LCMS: 521.2(M+H) + .

[0464] Step 2: N-(3-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 159, to obtain the title compound (yield 35%). 1 ¹H NMR (400 MHz, DMSO-d6): 9.79 (s, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.92 (s, 1H), 7.43-7.40 (m, 1H), 7.32-7.24 (m, 3H), 7.05-6.89 (m, 1H), 6.79 (s, 1H), 6.77 (s, 1H), 3.44-3.42 (m, 4H), 2.80-2.77 (m, 4H), 2.11 (s, 3H). NH and OH protons were not observed. LCMS: 407.2 (M + H) + .

[0465] Example 164 1-(3-fluoro-2'-hydroxy-3''-(piperazin-1-yl)-[1,1':3',1''-terphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0466] The title compound was prepared using tert-butyl 4-(3'-bromo-2'-methoxy-[1,1'-biphenyl]-3-yl)piperazine-1-carboxylate and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylimidazolidin-2-one, followed by BBr3, according to the procedure described for Example 159, to obtain the title compound. 1H NMR (400 MHz, DMSO-d6+D2O): 7.50 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 12.8, 1.6 Hz, 1H), 7.37-7.33 (m, 2H), 7.28-7.22 (m, 2H), 7.12 (s, 1H), 7.07-7.03 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 3.79 (t, J = 8.4 Hz, 2H), 3.51-3.47 (m, 2H), 3.41-3.38 (m, 4H), 3.26-3.24 (m, 4H), 2.78 (s, 3H).LCMS: 447.3 (M + H) + .

[0467] Example 165 N-(3'',5''-Dichloro-2'-Hydroxy-3-Methoxy-4''-(2-Oxopyrrolidine-1-yl)-[1,1':3',1''-Terphenyl]-4-yl)acetamide [ka]

[0468] The title compound was prepared using 1-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one and N-(3'-bromo-2'-hydroxy-3-methoxy-[1,1'-biphenyl]-4-yl)acetamide, following the procedure described for Example 42, to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6): 9.20 (s, 1H), 8.69 (s, 1H), 8.07-7.99 (m, 1H), 7.73 (s, 2H), 7.32-7.29 (m, 2H), 7.18 (s, 1H), 7.07-7.03 (m, 2H), 3.87 (s, 3H), 3.66 (t, J = 7.2 Hz, 2H), 2.50-2.45 (m, 2H), 2.26-2.21 (m, 2H), 2.11 (s, 3H). LCMS: 485.2 (M + H)+ .

[0469] [Table 17-1] [Table 17-2] [Table 17-3]

[0470] Example 172 1-(3,5-dichloro-2'-hydroxy-3'-(3-(piperazine-1-yl)isoxazole-5-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one [ka]

[0471] The title compound was prepared using 1-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one and 2-bromo-6-(3-(piperazin-1-yl)isoxazole-5-yl)phenol, following the procedure described for Example 51. 1 1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 2H), 7.65 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.35 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.72 (s, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 4.8 Hz, 4H), 2.84 (t, J = 4.8 Hz, 4H), 2.47-2.43 (m, 2H), 2.25-2.18 (m, 2H). No NH or OH protons were observed. LCMS: 473.2 (M + H) + .

[0472] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7] [Table 18-8] [Table 18-9] [Table 18-10] [Table 18-11] [Table 18-12] [Table 18-13] [Table 18-14]

[0473] Example 212 N-(3-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)thiazole-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0474] Step 1: tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)thiazole-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-bromothiazol-2-yl)piperazine-1-carboxylate and N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 1, and the title compound was obtained (yield 75%). LCMS: 527.2(M+H) + .

[0475] Step 2: N-(3-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)thiazole-4-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)thiazole-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 1. 1H NMR (400 MHz, DMSO-d6): δ 12.56 (s, 1H), 9.75 (s, 1H), 7.88 (t, J = 8.4 Hz, 2H), 7.73 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.46 (dd, J = 12.4 Hz, 1.2 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 3.37 (t, J = 4.4 Hz, 4H), 2.83 (t, J = 5.2 Hz, 4H), 2.10 (s, 3H). LCMS: 413.1 (M + H) + .

[0476] Example 213 1-(3-chloro-2'-hydroxy-3'-(pyridine-4-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one 2,2,2-trifluoroacetate [ka]

[0477] Step 1: N-(4-bromo-2-chlorophenyl)-4-chlorobutanamide To a solution of 4-bromo-2-chloroaniline (2.60 g, 12.6 mmol) in THF (30 mL), 4-chlorobutanoyl chloride (2.66 g, 18.9 mmol, 2.22 mL) and Na2CO3 (2.00 g, 18.9 mmol) were added. After addition, the reaction mixture was stirred under a nitrogen atmosphere at 84°C for 6 hours. After the reaction was confirmed by LC-MS, the reaction mixture was filtered, concentrated, diluted with H2O (50 mL), and extracted with EA (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a brown solid (3.9 g, yield 99%). LC-MS: 309.9(M+H) + .

[0478] Step 2: 1-(4-bromo-2-chlorophenyl)pyrrolidine-2-one To a solution of N-(4-bromo-2-chlorophenyl)-4-chlorobutanamide (2.00 g, 6.40 mmol) in THF (30 mL), NaH (282 mg, 7.04 mmol, 60 wt% of the mineral oil) was added. After addition, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was confirmed by LC-MS and TLC, the reaction mixture was quenched with H2O (80 mL) and extracted with EA (30 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a brown oil (1.3 g, yield 74%). LC-MS: 273.9 (M + H) + .

[0479] Step 3: 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one A mixture of 1-(4-bromo-2-chlorophenyl)pyrrolidine-2-one (1.30 g, 4.74 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.41 g, 9.47 mmol), KOAc (1.39 g, 14.2 mmol), and Pd(dppf)Cl2 (347 mg, 0.474 mmol) in dioxane (30 mL) was stirred overnight at 90°C under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 2:1) as eluents to obtain the title compound as a brown oily substance (1.4 g, yield 93%). LC-MS: 322.1(M+H) + .

[0480] Step 4: 1-(3'-bromo-3-chloro-2'-hydroxy-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one: A mixture of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one (500 mg, 1.55 mmol), 2-bromo-6-iodophenol (466 mg, 1.55 mmol)K3PO4 (989 mg, 4.66 mmol), and Pd(dppf)Cl2 (228 mg, 0.310 mmol) in dioxane:water (8:1, 15 mL) was stirred overnight at 40°C under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:1) as eluents to obtain the title compound as a brown solid (200 mg, yield 35%). LC-MS: 365.9(M+H) + .

[0481] Step 5: 1-(3-chloro-2'-hydroxy-3'-(pyridine-4-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one 2,2,2-trifluoroacetate: A mixture of 1-(3'-bromo-3-chloro-2'-hydroxy-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one (150 mg, 0.410 mmol), pyridine-4-ylboronic acid (201 mg, 1.64 mmol), K3PO4 (261 mg, 1.23 mmol), and Pd(dppf)Cl2 (60 mg, 0.080 mmol) in dioxane:water (8:1, 10 mL) was stirred at 110 °C for 4 hours under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane and methanol (DCM:MeOH = 15:1) as eluents to obtain the crude product. The crude product was purified by preparative HPLC using acetonitrile in water in the presence of TFA to obtain the title compound as a white solid (31.5 mg, yield 16%). 1H NMR (400 MHz, DMSO-d6) (TFA salt) 9.39 (1H), 8.87 (d, J = 3.2 Hz, 2H), 8.10 (s, 2H), 7.74 (d, J = 1.6 Hz, 1H), 7.57 (dd, J = 8.0, 1.6 Hz, 1H), 7.51-7.45 (m, 3H), 7.20-7.16 (m, 1H), 3.75-3.72 (m, 2H), 2.48-2.41 (m, 2H), 2.21-2.14 (m, 2H). LCMS: 365.2 (M + H) + .

[0482] Example 214 N-(3''-chloro-3-fluoro-2'-hydroxy-5''-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide [ka]

[0483] Step 1: tert-butyl 4-(3-bromo-5-chlorophenyl)piperazine-1-carboxylate To a solution of 1,3-dibromo-5-chlorobenzene (2.00 g, 7.40 mmol) and tert-butylpiperazine-1-carboxylate (459 mg, 2.47 mmol) in DMSO (25 mL), K2CO3 (1.02 g, 7.40 mmol), CuI (281 mg, 1.41 mmol), and (L)-proline (340 mg, 2.96 mmol) were added. The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the reaction mixture was cooled, H2O (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to obtain the residue. This residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 5:1) as the eluents to obtain the title compound as a white solid (200 mg, yield 22%). LCMS: 318.9(M-56+H)+ .

[0484] Step 2: tert-butyl 4-(4''-acetamido-5-chloro-3''-fluoro-2'-methoxy-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(3-bromo-5-chlorophenyl)piperazine-1-carboxylate (200 mg, 0.530 mmol), N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide (205 mg, 0.530 mmol), K3PO4 (337 mg, 1.59 mmol), and Pd(dppf)Cl2 (78 mg, 0.11 mmol) in dioxane:water (8:1, 10 mL) was stirred at 110 °C for 4 hours under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 4:1) as eluents, and the title compound was obtained as a yellow solid (200 mg, yield 68%). LCMS: 554.2(M+H) + .

[0485] Step 3: N-(3''-chloro-3-fluoro-2'-hydroxy-5''-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide To a solution of tert-butyl 4-(4''-acetamido-5-chloro-3''-fluoro-2'-methoxy-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate (200 mg, 0.360 mmol) in DCM (1 mL), BBr3 (5 mL, 17% in DCM) was added dropwise at 0°C. The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 4 hours. After the reaction was confirmed by LC-MS, the reaction mixture was quenched with MeOH (5 mL) at 0°C. The mixture was concentrated, and the residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (25.6 mg, yield 16%). 1 1H NMR (400 MHz, DMSO-d6): 9.78 (s, 1H), 7.94-7.90 (m, 1H), 7.42 (dd, J = 12.4, 1.2 Hz, 1H), 7.32-7.30 (m, 1H), 7.26-7.22 (m, 2H), 7.02-6.90 (m, 4H), 3.11 (d, J = 4.4 Hz, 4H), 2.82 (d, J = 4.4 Hz, 4H), 2.11 (s, 3H). No NH or OH protons were observed. LCMS: 440.2 (M + H) + .

[0486] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5] [Table 19-6] [Table 19-7] [Table 19-8] [Table 19-9] [Table 19-10] [Table 19-11] [Table 19-12] [Table 19-13]

[0487] Example 250 N-(2'-(difluoromethyl)-3-fluoro-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0488] Step 1: 1,3-Dibromo-2-(difluoromethyl)benzene To a solution of 2,6-dibromobenzaldehyde (1.00 g, 3.80 mmol) in DCM (40 mL), BAST (1.68 g, 7.60 mmol) was slowly added. After addition, the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, a saturated aqueous solution of NaHCO3 was added to the mixture at 0°C while being vigorously stirred. After stirring for 1 hour, the phases were separated, and the aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 10:1) as eluents, and the title compound was obtained as a colorless oil (860 mg, yield 80%). LC-MS: 285.1(M+H) + .

[0489] Step 2: N-(3'-bromo-2'-(difluoromethyl)-3-fluoro-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using 1,3-dibromo-2-(difluoromethyl)benzene and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 1. LCMS: 358.1(M+H) + .

[0490] Step 3: tert-butyl 4-(4-(4'-acetamido-2-(difluoromethyl)-3'-fluoro-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using N-(3'-bromo-2'-(difluoromethyl)-3-fluoro-[1,1'-biphenyl]-4-yl)acetamide and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate according to the procedure described for Example 1. LCMS: 541.2(M+H) + .

[0491] Step 4: N-(2'-(difluoromethyl)-3-fluoro-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide The reaction mixture was prepared by stirring the reaction mixture under a nitrogen atmosphere at room temperature for 4 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by preparative HPLC using acetonitrile in water in the presence of NH4HCO3 to obtain the title compound as a white solid (27.8 mg, yield 34%). 1 ¹H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.16 (d, J = 4.8 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.65-7.63 (m, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.27 (d, J = 11.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.73-6.59 (m, 3H), 3.45-3.43 (m, 4H), 2.79-2.77 (m, 4H), 2.12 (s, 3H). No NH or OH protons were observed. 19 F NMR (376 MHz, DMSO-d6): δ -101.03, -125.17. LCMS: 441.2 (M + H) + .

[0492] Example 251 (R)-N-(3-fluoro-2'-hydroxy-3'-(2-(3-hydroxypyrrolidine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0493] The title compound was prepared using N-(3-fluoro-3'-(2-fluoropyridine-4-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide, (R)-pyrrolidine-3-ol, and BBr3, following the procedure described for Example 163 (Scheme 17). 1 H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 8.51 (s, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.41 (dd, J = 12.4 Hz, 2.0 Hz, 1H), 7.31-7.24 (m, 3H), 7.02 (t, J = 7.6 Hz, 1H), 6.67 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 6.52 (s, 1H), 4.93 (d, J = 3.6 Hz, 1H), 4.39 (s, 1H), 3.53-3.45 (m, 3H), 3.34-3.31 (m, 1H), 2.10 (s, 3H), 2.07-1.99 (m, 1H), 1.91-1.87 (m, 1H). LCMS: 408.2 (M + H) + .

[0494] Example 252 (R)-1-(3-fluoro-2'-hydroxy-3'-(2-(3-methylpiperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one [ka]

[0495] Step 1: (R)-tert-butyl 4-(4-bromopyridine-2-yl)-2-methylpiperazine-1-carboxylate To a solution of (R)-tert-butyl 2-methylpiperazine-1-carboxylate (1.76 g, 10.0 mmol) and 4-bromo-2-fluoropyridine (2.0 g, 10 mmol) in DMSO (50 mL), K2CO3 (4.0 g, 30 mmol) was added. After addition, the reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the reaction mixture was filtered, concentrated, diluted with H2O (150 mL), and extracted with EA (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a colorless oil (2.1 g, yield 59%). LC-MS: 356.1(M+H) + .

[0496] Step 2: (R)-(2-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)pyridine-4-yl)boronic acid The title compound was prepared using (R)-tert-butyl 4-(4-bromopyridine-2-yl)-2-methylpiperazine-1-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described for Example 1, and the title compound was obtained (yield 44%). LCMS: 322.2(M+H) + .

[0497] Step 3: (R)-tert-butyl4-(4-(3-bromo-2-methoxyphenyl)pyridine-2-yl)-2-methylpiperazine-1-carboxylate The title compound was prepared using (R)-(2-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)pyridine-4-yl)boronic acid and 1,3-dibromo-2-methoxybenzene according to the procedure described in Example 1, and the title compound was obtained (yield 37%). LCMS: 462.1(M+H) + .

[0498] Step 4: (R)-tert-butyl4-(4-(3'-fluoro-2-methoxy-4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)-2-methylpiperazine-1-carboxylate The title compound was prepared using (R)-tert-butyl 4-(4-(3-bromo-2-methoxyphenyl)pyridine-2-yl)-2-methylpiperazine-1-carboxylate and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one according to the procedure described for Example 1, and the title compound was obtained (yield 69%). LCMS: 561.2(M+H) + .

[0499] Step 5: (R)-1-(3-fluoro-2'-hydroxy-3'-(2-(3-methylpiperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one The title compound was prepared using (R)-tert-butyl 4-(4-(3'-fluoro-2-methoxy-4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)-2-methylpiperazine-1-carboxylate and BBr3, following the procedure described for Example 214. 1H NMR (400 MHz, DMSO-d6): δ 8.13 (d, J = 4.8 Hz, 1H), 7.50-7.44 (m, 2H), 7.39 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.32-7.26 (m, 2H), 7.04 (t, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.77 (d, J = 5.2 Hz, 1H), 4.16-4.11 (m, 2H), 3.79 (t, J = 6.8 Hz, 2H), 2.95-2.92 (m, 1H), 2.71-2.66 (m, 3H), 2.45 (t, J = 8.0 Hz, 2H), 2.35-2.29 (m, 1H), 2.18-2.10 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). NH and OH protons were not observed. 19 F NMR (376 MHz, DMSO-d6): δ -120.24. LCMS: 447.3 (M + H) + .

[0500] Example 253 (R)-1-(3-chloro-2'-hydroxy-3'-(2-(3-methylpiperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one [ka]

[0501] The title compound was prepared using (R)-tert-butyl 4-(4-(3'-chloro-2-methoxy-4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)-2-methylpiperazine-1-carboxylate and BBr3 according to the procedure described for Example 252 to obtain the title compound (yield 61%). 1H NMR (2 TFA salt - 400 MHz, DMSO-d6): δ 9.05 (br s, 1H), 8.75 (br s, 2H), 8.20 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.55-7.53 (m, 1H), 7.48-7.46 (m, 1H), 7.36-7.31 (m, 2H), 7.12-7.07 (m, 2H), 6.96 (d, J = 5.2 Hz, 1H), 4.41-4.36 (m, 2H), 3.73 (t, J = 6.8 Hz, 2H), 3.42-3.32 (m, 2H), 3.16–3.07 (m, 2H), 2.97–2.91 (m, 1H), 2.45 (t, J = 8.0 Hz, 2H), 2.20–2.13 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). No NH or OH protons were observed. 19 F NMR (376 MHz, DMSO-d6): δ -74.39. LCMS: 463.3 (M + H) + .

[0502] [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8] [Table 20-9] [Table 20-10] [Table 20-11] [Table 20-12] [Table 20-13] [Table 20-14] [Table 20-15] [Table 20-16]

[0503] Example 296 N-(3'-(2-(3-aminopropane-1-in-1-yl)pyridine-4-yl)-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0504] Step 1: N-(3'-(2-chloropyridine-4-yl)-3-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide and 4-bromo-2-chloropyridine according to the procedure described for Example 214, yielding the title compound (65% yield). LCMS: 371.2(M+H) + .

[0505] Step 2: tert-butyl(3-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)prop-2-in-1-yl)carbamate A solution of N-(3'-(2-chloropyridine-4-yl)-3-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)acetamide (100 mg, 0.270 mmol), tert-butylpropa-2-in-1-yl carbamate (49.6 mg, 0.320 mmol), CuI (5.1 mg, 0.027 mmol), DIPEA (70 mg, 0.54 mmol), and PdCl2(PPh3)2 (19 mg, 0.027 mmol) in DMAC (5 mL) was stirred under microwave at 100 °C for 4 hours. After the reaction was completed by LC-MS, the reaction mixture was cooled, poured into H2O (20 mL), and extracted with DCM (20 mL x 3). The combined organic phase was washed with water (20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as the eluent to obtain the title compound as a black oily substance (65 mg, yield 49%). LCMS: 490.1(M+H) + .

[0506] Step 3: N-(3'-(2-(3-aminopropane-1-in-1-yl)pyridine-4-yl)-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl(3-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)propa-2-in-1-yl)carbamate and BBr3, following the procedure described for Example 214, to obtain the title compound (9% yield). 11H NMR (400 MHz, DMSO-d6): 9.80 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.65 (s, 1H), 7.52 (dd, J = 5.2, 2.0 Hz, 1H), 7.42 (dd, J = 5.2, 1.6 Hz, 1H), 7.34-7.31 (m, 3H), 7.07 (t, J = 7.6 Hz, 1H), 3.55 (s, 2H), 2.11 (s, 3H). No NH or OH protons were observed. LCMS: 376.2 (M + H) + .

[0507] Example 297 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0508] Step 1: tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-(3-bromo-5-fluoro-2-methoxyphenyl)pyridine-2-yl)piperazine-1-carboxylate and 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylimidazolidined-2-one according to the procedure described for Example 1, yielding the title compound (57% yield). LCMS: 596.2(M+H) + .

[0509] Step 2: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one: The title compound was prepared using tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 214, to obtain the title compound (48% yield). 1 1H NMR (400 MHz, DMSO-d6): 8.14 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.56-7.53 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.22-7.16 (m, 2H), 6.92 (s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 3.75-3.71 (m, 2H), 3.51-3.47 (m, 2H), 3.46-3.43 (m, 4H), 2.80-2.77 (m, 7H). NH and OH protons were not observed. LCMS: 482.2 (M + H) + .

[0510] Example 298 N-(3'-(2-(2,6-diazaspiro[3,3]heptan-2-yl)pyridine-4-yl)-3-chloro-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0511] Step 1: tert-butyl6-(4-(4'-acetamido-3'-chloro-5-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate The title compound was prepared using tert-butyl 6-(4-(3-bromo-5-fluoro-2-methoxyphenyl)pyridine-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and N-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 1. LCMS: 567.1(M+H) + .

[0512] Step 2: N-(3'-(2-(2,6-diazaspiro[3,3]heptan-2-yl)pyridine-4-yl)-3-chloro-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 6-(4-(4'-acetamido-3'-chloro-5-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and BBr3, following the procedure described for Example 214. 1 1H NMR (400 MHz, DMSO-d6): 9.58 (s, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.0, 1.6 Hz, 1H), 7.20-7.12 (m, 2H), 6.82 (d, J = 5.2 Hz, 1H), 6.54 (s, 1H), 4.03-4.02 (m, 4H), 3.66-3.64 (m, 4H), 2.12 (s, 3H). NH and OH protons were not observed. LCMS: 453.1 (M + H) + .

[0513] Example 299 4'-Acetamido-3'-Fluoro-6-hydroxy-N-methyl-5-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-3-carboxamide [ka]

[0514] Step 1: tert-butyl 4-(4-(3-bromo-2-methoxy-5-(methoxycarbonyl)phenyl)pyridine-2-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(4-(3-bromo-2-hydroxy-5-(methoxycarbonyl)phenyl)pyridine-2-yl)piperazine-1-carboxylate (100 mg, 0.203 mmol), CH3I (32.0 mg, 0.223 mmol), and K2CO3 (42.0 mg, 0.304 mmol) in acetone (10 mL) was stirred at 60°C for 3 hours. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate (4:1~1:1)) as eluents to obtain the title compound as a white solid (77 mg, yield 75%). LCMS: 506.0(M+H) + .

[0515] Step 2: tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-(3-bromo-2-methoxy-5-(methoxycarbonyl)phenyl)pyridine-2-yl)piperazine-1-carboxylate and N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide according to the procedure described for Example 1, yielding the title compound (83% yield). LCMS: 579.2(M+H) + .

[0516] Step 3: tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-5-(methylcarbamoyl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-5-(methoxycarbonyl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate (62 mg, 0.12 mmol) in CH3NH2 / EtOH (5 mL, 3 M) was stirred in a microwave at 150°C for 3 hours. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (2:1) as eluents to obtain the title compound as a white solid. LCMS: 578.0 (M+H) + .

[0517] Step 4: 4'-Acetamido-3'-Fluoro-6-Hydroxy-N-methyl-5-(2-(Piperazin-1-yl)pyridine-4-yl)-[1,1'-Biphenyl]-3-Carboxamide The title compound was prepared using tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-5-(methylcarbamoyl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 214. 1H NMR (400 MHz, DMSO-d6): 9.80 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.95-7.94 (m, 1H), 7.75 (dd, J = 16.8, 2.4 Hz, 2H), 7.49 (d, J = 12.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J = 5.2 Hz, 1H), 3.47-3.43 (m, 4H), 2.83-2.80 (m, 4H), 2.77 (d, J = 4.0 Hz, 3H), 2.11 (s, 3H). No NH and OH protons were observed. LCMS: 464.2 (M + H) + .

[0518] [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5] [Table 21-6]

[0519] Example 317 1-(3-chloro-2'-hydroxy-4''-(hydroxymethyl)-3''-(piperazin-1-yl)-[1,1':3',1''-terphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0520] Step 1: tert-butyl 4-(3''-chloro-4-formyl-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate and 1-(3-chloro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 1, and the title compound was obtained (yield 77%). LCMS: 605.2(M+H) + .

[0521] Step 2: tert-butyl 4-(3''-chloro-4-(hydroxymethyl)-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3''-chloro-4-formyl-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate (100 mg, 0.166 mmol) in MeOH (3 mL), NaBH4 (12.6 mg, 0.330 mmol) was added at 0°C. The reaction mixture was stirred at room temperature under N2 for 3 hours. After the reaction was shown by LC-MS, H2O was added to the reaction product and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (PE:EA = 1:2) to obtain the title compound as a white solid (80 mg, yield 80%). LCMS: 607.6 (M+H) + .

[0522] Step 3: 1-(3-chloro-2'-hydroxy-4''-(hydroxymethyl)-3''-(piperazin-1-yl)-[1,1':3',1''-terphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(3''-chloro-4-(hydroxymethyl)-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3, to obtain the title compound (11% yield). 1 1H NMR (400 MHz, DMSO-d6): 7.67 (d, J = 1.6 Hz, 1H), 7.53-7.50 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.26-7.19 (m, 4H), 7.04 (d, J = 7.6 Hz, 1H), 5.14-5.13 (m, 1H), 4.58 (s, 2H), 3.74-3.70 (m, 2H), 3.51-3.47 (m, 2H), 3.19-2.91 (m, 8H), 2.77 (s, 3H). NH and OH protons were not observed. LCMS: 493.2 (M + H) + .

[0523] Example 318 1-(3-chloro-6'-hydroxy-5'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1':3',1''-terphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0524] The title compound was prepared using [1,1'-biphenyl]-4-ol, 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylimidazolidin-2-one, and (2-(4-(tert-butoxycarbonyl)piperazine-1-yl)pyridine-4-yl)boronic acid, following the procedure described for Example 298, to obtain the title compound (yield 34%). 1 H NMR (400 MHz, DMSO-d6): 8.16 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (dd, J = 15.2, 2.4 Hz, 2H), 7.47-7.41 (m, 3H), 7.32 (t, J = 7.2 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 5.2 Hz, 1H), 3.75-3.72 (m, 2H), 3.51-3.46 (m, 6H), 2.79–2.78 (m, 7H). No NH and OH protons were observed. LCMS: 540.3 (M + H) + .

[0525] Example 319 1-(4''-(aminomethyl)-3-chloro-2'-hydroxy-3''-(piperazin-1-yl)-[1,1':3',1''-terphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0526] Step 1: tert-butyl 4-(3''-chloro-4-((hydroxyimino)methyl)-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3''-chloro-4-formyl-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate (130 mg, 0.220 mmol) in EtOH (6 mL), NH2-OH·HCl (45 mg, 0.65 mmol) and NaOAc (53 mg, 0.65 mmol) were added. The reaction mixture was stirred at room temperature under N2 for 6 hours. After the reaction was completed by LC-MS, H2O (50 mL) was added to the reaction product and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (130 mg, yield 96%) as a white solid, which was used in the next step without further purification. LCMS: 620.6 (M+H) + .

[0527] Step 2: tert-butyl 4-(4-(aminomethyl)-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3''-chloro-4-((hydroxyimino)methyl)-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate (134 mg, 2.10 mmol) in acetic acid (4 mL), Zn (134 mg, 2.10 mmol) was added. The reaction mixture was stirred under N2 at 70°C for 16 hours. After the reaction was completed by LC-MS, the reaction mixture was filtered and concentrated. The residue was adjusted to pH 9-11 with saturated NaHCO3 and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (110 mg, yield 87%) as a pale yellow solid, which was used in the next step without further purification. LCMS: 606.6 (M+H) + .

[0528] Step 3: 1-(4''-(aminomethyl)-3-chloro-2'-hydroxy-3''-(piperazin-1-yl)-[1,1':3',1''-terphenyl]-4-yl)-3-methylimidazolidined-2-one 2,2,2-trifluoroacetate The title compound was prepared using tert-butyl 4-(4-(aminomethyl)-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 214, to obtain the title compound (yield 35%). 1 H NMR (400 MHz, DMSO-d6): 8.90 (br s, 2H), 8.65 (s, 1H), 8.16-8.15 (m, 3H), 7.68 (d, J = 1.6 Hz, 1H), 7.53-7.41 (m, 5H), 7.30-7.27 (m, 2H), 7.09-7.07 (m, 1H), 4.16-4.14 (m, 2H), 3.75-3.71 (m, 2H), 3.51-3.47 (m, 2H), 3.32-3.30 (m, 4H), 3.10-3.08 (m, 4H), 2.77 (s, 3H). LCMS: 492.2 (M + H) + .

[0529] Example 320 N-((3''-chloro-2'-hydroxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-3-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-4-yl)methyl)acetamide [ka]

[0530] Step 1: tert-butyl 4-(4-(acetamidomethyl)-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3''-terphenyl]-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-(aminomethyl)-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate (40 mg, 0.066 mmol) in DCM (1 mL), TEA (20.0 mg, 0.198 mmol) and CH3COCl (8.0 mg, 0.099 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under N2 for 2 hours. After the reaction was completed by LC-MS, the reaction mixture was diluted with H2O (15 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (40 mg, yield 94%) as a pale yellow solid, which was used in the next step without further purification. LCMS: 648.7 (M+H) + .

[0531] Step 2: N-((3''-chloro-2'-hydroxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-3-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-4-yl)methyl)acetamide The title compound was prepared using tert-butyl 4-(4-(acetamidomethyl)-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 214. 11H NMR (400 MHz, DMSO-d6): 8.23 ​​(d, J = 5.6 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.0, 1.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.29-7.21 (m, 5H), 7.03 (t, J = 7.6 Hz, 1H), 4.36 (d, J = 5.2 Hz, 2H), 3.74-3.70 (m, 2H), 3.51-3.47 (m, 2H), 2.88-2.77 (m, 11H), 1.91 (s, 3H). No NH or OH protons were observed. LCMS: 534.2 (M + H) + .

[0532] [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4]

[0533] Example 328 1-(3-chloro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylpyrrolidine-2-one [ka]

[0534] Step 1: 1-(4-bromo-2-chlorophenyl)-3-methylpyrrolidine-2-one To a solution of 1-(4-bromo-2-chlorophenyl)pyrrolidine-2-one (500 mg, 1.82 mmol) in THF (9 mL), LiHMDS (2 mL, 2 mmol, 1 M in THF) was added under N2 at -78°C. The reaction mixture was then stirred under N2 at -78°C for 1 hour. CH3I (312 mg, 2.20 mmol) was added under N2 at -78°C. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. After the reaction was completed by LC-MS, the reaction mixture was quenched with aqueous NH4Cl solution and extracted with EA (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound as a brown oil (500 mg, 95% yield). LC-MS: 288.0(M+H) + .

[0535] Step 2: 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyrrolidine-2-one The title compound was prepared using 1-(4-bromo-2-chlorophenyl)-3-methylpyrrolidine-2-one and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described for Example 1, yielding the title compound (60% yield). LCMS: 336.3(M+H) + .

[0536] Step 3: tert-butyl 4-(4-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyrrolidine-2-one and tert-butyl 4-(4-(3-bromo-2-hydroxyphenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 1, to obtain the title compound (yield 59%). LCMS: 563.3(M+H) +.

[0537] Step 4: 1-(3-chloro-2'-hydroxy-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylpyrrolidine-2-one To a solution of tert-butyl 4-(4-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate (150 mg, 0.266 mmol) in DCM (2 mL), TFA (2 mL) was added. The reaction mixture was then stirred under N2 at room temperature for 4 hours. After the reaction was completed by LC-MS, the reaction mixture was concentrated. The residue was purified by preparative HPLC to obtain the title compound as a pale yellow solid (23.7 mg, yield 19%). 1 H NMR (400 MHz, DMSO-d6): 8.14 (d, J = 4.8 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.30 (dd, J =10.4, 7.6 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.78 (d, J = 5.2 Hz, 1H), 3.70-3.61 (m, 2H), 3.45-3.43 (m, 4H), 2.80-2.78 (m, 4H), 2.63–2.57 (m, 1H), 2.43–2.35 (m, 1H), 1.83–1.78 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H). No NH or OH protons were observed. LCMS: 463.2 (M + H) + .

[0538] Example 329 1-(3-chloro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3,3-dimethylpyrrolidine-2-one [ka]

[0539] The title compound was prepared using tert-butyl 4-(4-(3'-chloro-4'-(3,3-dimethyl-2-oxopyrrolidine-1-yl)-2-hydroxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 328. 1 H NMR (400 MHz, DMSO-d6): 8.13 (d, J = 5.2 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.54 (dd, J = 8.0, 1.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.30 (dd, J =11.2, 7.2 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.78 (d, J = 4.8 Hz, 1H), 3.66 (t, J = 7.2 Hz, 2H), 3.45-3.43 (m, 4H), 2.80-2.78 (m, 4H), 2.05 (d, J = 6.4 Hz, 2H), 1.18 (s, 6H). NH and OH protons were not observed. LCMS: 477.1 (M + H) + .

[0540] Example 330 N-(3''-chloro-2'-hydroxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-3-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide [ka]

[0541] Step 1: tert-butyl4-(4-acetamido-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(2-acetamido-5-bromophenyl)piperazine-1-carboxylate and 1-(3-chloro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 1, and the title compound was obtained (yield 82%). LCMS: 634.0(M+H) + .

[0542] Step 2: N-(3''-chloro-2'-hydroxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-3-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 4-(4-acetamido-3''-chloro-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3. 1H NMR (400 MHz, DMSO-d6): 8.83 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.27-7.20 (m, 4H), 7.03 (t, J = 8.0 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.49 (t, J = 8.4 Hz, 2H) 2.91-2.89 (m, 4H), 2.78-2.76 (m, 7H), 2.14 (s, 3H). No NH or OH protons were observed. LCMS: 520.2 (M + H) + .

[0543] Example 331 3''-Chloro-2'-hydroxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-5-(piperazine-1-yl)-[1,1':3',1''-terphenyl]-3-carbonitrile [ka]

[0544] Step 1: tert-butyl 4-(3''-chloro-5-cyano-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate The title compound was prepared using 1-(3-chloro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one and tert-butyl 4-(3-bromo-5-cyanophenyl)piperazine-1-carboxylate according to the procedure described for Example 1, yielding the title compound (45% yield). LCMS: 602.2(M+H) + .

[0545] Step 2: 3''-Chloro-2'-hydroxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-5-(piperazin-1-yl)-[1,1':3',1''-terphenyl]-3-carbonitrile The title compound was prepared using tert-butyl 4-(3''-chloro-5-cyano-2'-methoxy-4''-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1':3',1''-terphenyl]-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3, to obtain the title compound (18% yield). 1 1H NMR (400 MHz, DMSO-d6): 7.68 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32-7.28 (m, 5H), 7.05 (t, J = 7 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.49 (t, J = 7.6 Hz, 2H), 3.18-3.16 (m, 4H), 2.84-2.82 (m, 4H), 2.77 (s, 3H). No NH or OH protons were observed. LCMS: 488.2 (M + H) + .

[0546] Example 332 1-(3-chloro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0547] Step 1: 1-(3'-bromo-3-chloro-2'-methoxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using 1,3-dibromo-2-methoxy-5-(trifluoromethyl)benzene and 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylimidazolidined-2-one according to the procedure described for Example 1. LCMS: 463.0(M+H) +

[0548] Step 2: tert-butyl4-(4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-(3'-bromo-3-chloro-2'-methoxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 1. LCMS: 646.2(M+H) + .

[0549] Step 3: 1-(3-chloro-2'-hydroxy-3'-(2-(piperazin-1-yl)pyridine-4-yl)-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3. 1H NMR (400 MHz, DMSO-d6): 9.65 (s, 1H), 8.79 (br s, 2H), 8.23 ​​(d, J = 5.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.64-7.59 (m, 2H), 7.57-7.54 (m, 1H), 7.50-7.48 (m, 1H), 7.09 (s, 1H), 6.96 (d, J = 4.8 Hz, 1H), 3.78-3.72 (m, 6H), 3.52-3.48 (m, 2H), 3.21-3.20 (m, 4H), 2.78 (s, 3H). LCMS: 532.2 (M + H) + .

[0550] Example 333 N-(3-fluoro-2'-hydroxy-3'-(2-((2-hydroxyethyl)amino)-6-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0551] Step 1: tert-butyl 4-(6-((2-hydroxyethyl)amino)-4-iodopyridine-2-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(6-fluoro-4-iodopyridine-2-yl)piperazine-1-carboxylate (407 mg, 1.00 mmol) and 2-aminoethanol (610 mg, 10.0 mmol) in EtOH (2 mL) was stirred at 90°C under nitrogen for 2 days. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (6 mL) and extracted with ethyl acetate (3 mL x 4). The combined organic phases were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated to obtain the residue. This residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (10:1~2:1) as eluents, and the title compound was obtained as an orange solid. LC-MS: 449.0 (M+H) + .

[0552] Step 2: tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-6-((2-hydroxyethyl)amino)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(6-((2-hydroxyethyl)amino)-4-iodopyridine-2-yl)piperazine-1-carboxylate and N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described in Example 1 (yield 67%). LCMS: 580.2(M+H) + .

[0553] Step 3: N-(3-fluoro-2'-hydroxy-3'-(2-((2-hydroxyethyl)amino)-6-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-6-((2-hydroxyethyl)amino)pyridine-2-yl)piperazine-1-carboxylate and BBr3 according to the procedure described in Example 3 to obtain the title compound (yield 3%). 1H NMR (400 MHz, DMSO-d6): 9.76 (s, 1H), 7.91 (t, J = 8.4 Hz, 1H), 7.39 (d, J = 12.4 Hz, 1H), 7.30-7.23 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.16 (t, J = 6.4 Hz, 1H), 5.95 (d, J = 16.0 Hz, 2H), 4.64 (t, J = 6.4 Hz, 1H), 3.53 (t, J = 5.2 Hz, 2H), 3.40-3.39 (m, 4H), 3.31-3.30 (m, 2H), 2.82-2.81 (m, 4H), 2.11 (s, 3H). NH and OH protons were not observed. LCMS: 466.2 (M + H) + .

[0554] [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4]

[0555] Example 342 5-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-3-(piperazine-1-yl)pyridine-2(1H)-one [ka]

[0556] Step 1: tert-butyl 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate To a solution of 3,5-dibromo-1-methylpyridine-2(1H)-one (267 mg, 1.00 mmol) and tert-butylpiperazine-1-carboxylate (186 mg, 1.00 mmol) in dioxane (10 mL), Pd(dba)3 (91.6 mg, 0.10 mmol), xanthophos (116 mg, 0.20 mmol), and Cs2CO3 (652 mg, 2.00 mmol) were added. After addition, the reaction mixture was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled, DCM (100 mL) was added, and the mixture was filtered. The filtrate was concentrated to obtain the residue, which was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as the eluent to obtain the title compound as a yellow solid (110 mg, yield 30%). LCMS: 372.1 (M+H) + .

[0557] Step 2: tert-butyl4-(5-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using (tert-butyl 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate and 1-(3-chloro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described in Example 1, and the title compound was obtained: LCMS: 608.7(M+H) + .

[0558] Step 3: 5-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-3-(piperazine-1-yl)pyridine-2(1H)-one The title compound was prepared using tert-butyl 4-(5-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3, to obtain the title compound (yield 37%). 1 ¹H NMR (400 MHz, DMSO-d6): 7.66 (d, J = 2.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 7.6 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 3.74-3.70 (m, 2H), 3.51-3.47 (m, 5H), 3.02-3.01 (m, 4H), 2.82-2.77 (m, 7H). No two NH or OH protons were observed. LCMS: 494.2 (M + H) + .

[0559] Example 343 1-(3-chloro-2'-hydroxy-3'-(6-(piperazin-1-yl)pyridazin-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0560] Step 1: 1-(3-chloro-3'-(6-chloropyridazine-4-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using 5-bromo-3-chloropyridazine and 1-(3-chloro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described in Example 1. LCMS: 429.3(M+H) + .

[0561] Step 2: tert-butyl 4-(5-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridazin-3-yl)piperazine-1-carboxylate The title compound was prepared using 1-(3-chloro-3'-(6-chloropyridazine-4-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one and tert-butylpiperazine-1-carboxylate, following the procedure described for Example 163. LCMS: 579.6(M+H) + .

[0562] Step 3: 1-(3-chloro-2'-hydroxy-3'-(6-(piperazin-1-yl)pyridazin-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(5-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridazin-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3. 11H NMR (400 MHz, DMSO-d6): 8.71 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.53-7.51 (m, 1H), 7.46-7.44 (m, 1H), 7.38-7.34 (m, 2H), 7.31 (s, 1H), 7.09-7.05 (m, 1H), 3.74-3.71 (m, 2H), 3.56-3.47 (m, 6H), 2.83-2.81 (m, 4H), 2.77 (m, 3H). NH and OH protons were not observed. LCMS: 465.1 (M + H) + .

[0563] [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5]

[0564] Example 356 1-(3-chloro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methyl-1H-pyrrole-2(5H)-one [ka]

[0565] Step 1: tert-butyl 4-(4-(3-bromo-2-methoxyphenyl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate and 1,3-dibromo-2-methoxybenzene, following the procedure described for Example 159. LCMS: 448.3(M+H) + .

[0566] Step 2: tert-butyl 4-(4-(2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-(3-bromo-2-methoxyphenyl)pyridine-2-yl)piperazine-1-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described in Example 159. LCMS: 496.6(M+H) + .

[0567] Step 3: N-allyl-4-bromo-2-chloroaniline 3-bromopropa-1-ene (6.60 g, 54.5 mmol) was added to a solution of 4-bromo-2-chloroaniline (7.5 g, 36 mmol) and Na2CO3 (7.7 g, 72 mmol) in DMF (80 mL). The reaction mixture was stirred at 80°C for 16 hours under N2. After the reaction was completed by LC-MS, the reaction product was cooled to room temperature, filtered, water (400 mL) was added, and extraction was performed with PE (100 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the title compound (5.0 g, yield 56%, purity 50%) as a colorless oil, which was used in the next step without further purification.

[0568] Step 4: N-allyl-N-(4-bromo-2-chlorophenyl)methacrylamide To a solution of N-allyl-4-bromo-2-chloroaniline (1.0 g, 4.0 mmol) in DCM (20 mL), TEA (1.24 g, 12.3 mmol) and methacryloyl chloride (637 mg, 6.10 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under N2 for 16 hours. After the reaction was completed by LC-MS, the reaction mixture was concentrated. The residue was purified by silica gel chromatography using dichloromethane and methanol (5:1) as eluents to obtain the title compound as a colorless oil (750 mg, yield 59%). LC-MS: 314.1(M+H) + .

[0569] Step 5: 1-(4-bromo-2-chlorophenyl)-3-methyl-1H-pyrrole-2(5H)-one A solution of N-allyl-N-(4-bromo-2-chlorophenyl)methacrylamide (750 mg, 2.4 mmol) in toluene (24 mL) was mixed with a second-generation Grubbs catalyst (101 mg, 0.120 mmol). The reaction mixture was stirred at 80°C for 3 hours under N2. After the reaction was completed by LC-MS, the reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography using dichloromethane and methanol (3:1) as eluents to obtain the title compound as a brown solid (630 mg, 92% yield). LC-MS: 286.1(M+H) + .

[0570] Step 6: tert-butyl 4-(4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-(4-bromo-2-chlorophenyl)-3-methyl-1H-pyrrole-2(5H)-one and tert-butyl 4-(4-(2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate according to the procedure described for Example 1, yielding the title compound (20% yield). LCMS: 575.6(M+H) + .

[0571] Step 7: 1-(3-chloro-2'-hydroxy-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methyl-1H-pyrrole-2(5H)-one The title compound was prepared using tert-butyl 4-(4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 3. 1 H NMR (TFA salt - 400 MHz, DMSO-d6): 8.92-8.89 (m, 3H), 8.20 (d, J = 5.6 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.55-7.51(m, 2H), 7.38-7.34 (m, 2H), 7.17-7.01 (m, 4H), 4.32-4.31 (m, 2H), 3.81-3.80 (m, 4H), 3.23-3.22 (m, 4H), 1.87 (d, J = 1.2 Hz, 3H). LCMS: 461.2 (M + H) + .

[0572] [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4]

[0573] Example 365 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methyl-1H-imidazole-2(3H)-one [ka]

[0574] Step 1: 1-(4-bromo-2-chlorophenyl)-3-(2,2-dimethoxyethyl)urea To a solution of 4-bromo-2-chloroaniline (10.0 g, 48.4 mmol) in THF (400 mL), TEA (40 mL, 0.29 mol) and bis(trichloromethyl)carbonate (7.20 g, 24.7 mmol) were slowly added at 0°C under N2. The reaction mixture was stirred at 0°C for 3 hours. Then, 2,2-dimethoxyethaneamine (6.10 g, 0.0581 mol) was added at 0°C. The reaction mixture was stirred overnight at room temperature. Four other batches were completed in parallel. The five batches were combined and concentrated together to obtain the title compound (81.4 g, 100%) as a white solid. 1 H NMR (400 MHz, CDCl3): 8.06 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.13 (br s, 1H), 5.18 (br s, 1H), 4.43 (t, J = 4.8 Hz, 1H), 3.44-3.41 (m, 8H).

[0575] Step 2: 1-(4-bromo-2-chlorophenyl)-1H-imidazole-2(3H)-one A solution of 1-(4-bromo-2-chlorophenyl)-3-(2,2-dimethoxyethyl)urea) (75 g, 0.222 mol) in MeOH (250 mL) was subsequently mixed with H2O (250 mL) and concentrated aqueous HCl (1 L). The mixture was then stirred at room temperature for 16 hours. The pH of the residue was adjusted to approximately 9-11 by adding aqueous NaOH, methanol was evaporated, and the residue was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound as a pale yellow solid (56 g, yield 92.2%). 1 H NMR (400 MHz, CDCl3): 10.14 (br s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 6.38 (s, 1H).

[0576] Step 3: 1-(4-bromo-2-chlorophenyl)-3-methyl-1H-imidazole-2(3H)-one To a solution of 1-(4-bromo-2-chlorophenyl)-1H-imidazole-2(3H)-one (69.4 g, 0.254 mol) in THF (650 mL), NaH (60%, 25.5 g, 0.638 mol) was gradually added at 0°C under N2. The reaction mixture was stirred at 0°C for 1 hour. Then, CH3I (47.6 mL, 0.765 mol) was added at 0°C. The reaction mixture was stirred overnight at room temperature. H2O (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine and concentrated to obtain the title compound as a white solid (72.9 g, 99% yield). 1 H NMR (400 MHz, CDCl3): 7.66 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 8.4, 2.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 6.32 (d, J = 3.2 Hz, 1H), 1.63 (s, 3H).

[0577] Step 4: tert-butyl 4-(4-(3-bromo-5-fluoro-2-methoxyphenyl)pyridine-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate (3 g, 7.7 mmol, commercially available) and 1,3-dibromo-5-fluoro-2-methoxybenzene (11 g, 38.6 mmol, commercially available) in dioxane / H2O (8:1, 50 mL), K3PO4 (4.91 g, 23.2 mmol) and Pd(dppf)Cl2 (1.13 g, 1.54 mmol) were added at room temperature under N2. The reaction mixture was stirred under N2 at 110 °C for 4 hours. The reaction mixture was cooled and concentrated. The residue was purified by flash column chromatography using (PE:EA=5:1) on silica gel to obtain the title compound (1.6 g, 45%) as a pale yellow solid. LCMS:466 / 468(M+H) + .

[0578] Step 5: tert-butyl 4-(4-(3-bromo-5-fluoro-2-methoxyphenyl)pyridine-2-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(4-(3-bromo-5-fluoro-2-methoxyphenyl)pyridine-2-yl)piperazine-1-carboxylate (1.6 g, 3.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.29 g, 5.1 mmol), KOAc (1.01 g, 10.3 mmol), and Pd(dppf)Cl2 (251 mg, 0.34 mmol) in dioxane (20 mL) was stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated and purified by silica gel chromatography using petroleum ether and ethyl acetate (5:1) as the eluent to obtain the title compound as a yellow solid (1.6 g, yield 91%). LCMS: 514(M+H) + .

[0579] Step 6: tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate (179 mg, 0.35 mmol) and 1-(4-bromo-2-chlorophenyl)-3-methyl-1H-imidazole-2(3H)-one (100 mg, 0.35 mmol), K3PO4 (221 mg, 1.04 mmol) and Pd(dppf)Cl2 (51 mg, 0.07 mmol) were added at room temperature under N2. The reaction mixture was stirred under N2 at 110°C for 4 hours. The reaction mixture was cooled and concentrated. The residue was purified by flash column chromatography (100% EA) to obtain the title compound (208 mg, 53%) as a pale yellow solid. LCMS: 594.6(M+H) + .

[0580] Step 7: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methyl-1H-imidazole-2(3H)-one To a solution of tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate (110 mg, 0.185 mol) in DCM (1 mL), BBr3 (1 M solution in DCM, 5 mL) was added under N2 at 0°C. The reaction mixture was stirred at room temperature for 4 hours. Then, MeOH (5 mL) was added to quench the reaction. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound as a green solid (88.9 mg, yield 30%).1 H NMR (400 MHz, DMSO-d6): 8.14 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 8.0 Hz 1H), 7.25-7.17 (m, 2H), 6.93 (s, 1H), 6.82 (dd, J = 0.8, 5.2 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 3.46-3.43 (m, 4H), 3.21 (s, 3H), 2.79-2.77 (m, 4H). LCMS: 480.2 (M + H) + .

[0581] Example 366 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methyl-1,5-dihydro-2H-pyrrole-2-one [ka]

[0582] Step 1: tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-(4-bromo-2-chlorophenyl)-3-methyl-1H-pyrrole-2(5H)-one and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 365, to obtain the title compound (yield 58%). LCMS: 593.6(M+H) + .

[0583] Step 2: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methyl-1H-pyrrole-2(5H)-one 2,2,2-trifluoroacetate The title compound was prepared using tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 365, to obtain the title compound (yield 21%). 1 H NMR (400 MHz, DMSO-d6- TFA salt): 8.83-8.75 (m, 3H), 8.21 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.60-7.53 (m, 2H), 7.29-7.21 (m, LCMS: 479.2 (M+H) + .

[0584] Example 367 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-(propa-2-in-1-yl)imidazolidin-2-one [ka]

[0585] Step 1: tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate and 1-(4-bromo-2-chlorophenyl)imidazolidin-2-one according to the procedure described for Example 365, yielding the title compound (47% yield). LCMS: 582.6(M+H) + .

[0586] Step 2: tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(2-oxo-3-(propa-2-in-1-yl)imidazolidin-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate (100 mg, 0.170 mmol) in THF (4 mL), NaH (17 mg, 0.43 mmol, 60 wt% in mineral oil) was added. The reaction mixture was stirred under a nitrogen atmosphere at 0°C for 1 hour, and then 3-bromopropa-1-yin (61 mg, 0.52 mmol) was added to the mixture. After the addition was complete, the reaction mixture was stirred overnight under a nitrogen atmosphere at room temperature. After the reaction was confirmed by LC-MS, the reaction mixture was quenched with H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a brown solid (100 mg, 95% yield). LC-MS: 620.7(M+H) + .

[0587] Step 3: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-(propa-2-in-1-yl)imidazolidin-2-one Using tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(2-oxo-3-(propa-2-in-1-yl)imidazolidin-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, the title compound was prepared according to the procedure described for Example 365 to obtain the title compound (11%). 1 H NMR (400 MHz, DMSO-d6- TFA salt): 8.85-8.72 (m, 3H), 8.21 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.51-7.48 (m, 1H), 7.26-7.20 (m, 2H), 7.09 (s, 1H), 6.98 (d, J = 5.2 Hz, 1H), 4.04 (d, J = 2.4 Hz, 2H), 3.77-3.75 (m, 6H), 3.57-3.53 (m, 2H), 3.30 (t, J = 2.0 Hz, 1H), 3.20 (s, 4H). LCMS: 506.2 (M + H) + .

[0588] Example 368 1-(3-chloro-3'-(2-cyclopropyl-6-(piperazine-1-yl)pyridine-4-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0589] Step 1: tert-butyl 4-(6-chloro-4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate A solution of 1-(3-chloro-3'-(2,6-dichloropyridine-4-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidine-2-one (400 mg, 0.738 mmol) and tert-butylpiperazine-1-carboxylate (242 mg, 1.30 mmol) in DMSO (8 mL) in a sealed tube was degassed using a nitrogen stream. The reaction mixture was then stirred at 150°C for 4 hours under microwave irradiation. After the reaction was completed by LC-MS, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the residue, which was diluted with H2O (16 mL) and extracted with EA (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (10:1-2:1) as eluents to obtain the title compound as an earthy yellow solid (161 mg, 36% yield). LCMS: 612.3(M+H) + .

[0590] Step 2: tert-butyl 4-(4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-6-cyclopropylpyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(6-chloro-4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and cyclopropylboronic acid, following the procedure described for Example 365, to obtain the title compound (70% yield). LCMS: 618.2(M+H) + .

[0591] Step 3: 1-(3-chloro-3'-(2-cyclopropyl-6-(piperazin-1-yl)pyridine-4-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-6-cyclopropylpyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 365, to obtain the title compound (yield 35%). 1 H NMR (400 MHz, DMSO-d6- TFA salt): 8.78 (s, 2H), 8.62 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.31 (dd, J = 2.0, 7.6 Hz, 1H), 7.26 (dd, J = 1.2, 7.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 3.74-7.68 (m, 6H), 3.48 (t, J = 8.0 Hz, 2H), 3.17 (s, 4H), 2.77 (s, 3H), 2.05-1.99 (m, 1H), 0.93-0.89 (m, 4H). LCMS: 504.2 (M + H) + .

[0592] Example 369 1-(3-chloro-2'-hydroxy-3'-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0593] Step 1: tert-butyl8-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate The title compound was prepared using 1-(3-chloro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one and tert-butyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate according to the procedure described for Example 342, yielding the title compound (60% yield). LCMS: 587.3(M+H) + .

[0594] Step 2: 1-(3-chloro-2'-hydroxy-3'-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 8-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate and BBr3, following the procedure described for Example 342, to obtain the title compound (3% yield). 1 H NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.44-7.42 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.15 (dd, J = 1.2, 8.4 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 3.89 (s, 2H), 3.74-3.70 (m, 2H), 3.48 (t, J = 8.0 Hz, 2H), 3.05 (t, J = 5.6 Hz, 2H), 2.77 (s, 3H), 2.72-2.67 (m, 2H). NH and OH protons were not observed. LCMS: 473.3 (M + H) + .

[0595] Example 370 N-((5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)pyridine-2-yl)methyl)acetamide [ka]

[0596] Step 1: tert-butyl 4-(5-bromo-2-cyanopyridine-3-yl)piperazine-1-carboxylate A mixture of 5-bromo-3-fluoropicolinonitrile (500 mg, 2.49 mmol), tert-butylpiperazine-1-carboxylate (1.39 g, 7.46 mmol), and K2CO3 (860 mg, 6.22 mmol) in Tol (30 mL) was stirred at 125°C for 12 hours under a nitrogen atmosphere. After the reaction was confirmed by LC-MS, the reaction mixture was cooled, water (30 mL) was added, and the mixture was extracted with EA (20 mL x 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as eluents to obtain the title compound as a white solid (630 mg, yield 69%). LC-MS: 369.1(M+H) + .

[0597] Step 2: tert-butyl 4-(2-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-2-cyanopyridine-3-yl)piperazine-1-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described for Example 368, yielding the title compound (86% yield). LCMS: 415.3(M+H) + .

[0598] Step 3: tert-butyl4-(5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-cyanopyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(2-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)piperazine-1-carboxylate and 1-(3'-bromo-3-chloro-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 368, yielding the title compound (57% yield). LCMS: 607.3(M+H) + .

[0599] Step 4: tert-butyl4-(2-amino-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate Raney-Ni (860 mg, 6.22 mmol) was added to a solution of tert-butyl 4-(5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-cyanopyridine-3-yl)piperazine-1-carboxylate (500 mg, 2.49 mmol) in EtOH (30 mL). The reaction mixture was stirred at room temperature under an H2 atmosphere for 4 hours. After the reaction was completed by LC-MS, the reaction mixture was filtered. The filtrate was concentrated to obtain the title compound as a white solid (60 mg, yield 50%). LC-MS: 611.3(M+H) + .

[0600] Step 5: tert-butyl4-(2-(acetamidomethyl)-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(2-amino-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate (60 mg, 0.098 mmol) in DCM (2 mL), TEA (15 mg, 0.15 mmol) and AcCl (7.7 mg, 0.098 mmol) were added dropwise. The reaction mixture was stirred at -78°C for 30 minutes. After the reaction was complete by LC-MS, water (10 mL) was added to the reaction mixture and extracted with DCM (10 mL x 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain the residue, which was diluted with 3 mL of a mixture of THF:MeOH:H2O (1:1:1) and NaOH (40 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then the pH of the mixture was adjusted to 7 with 1 M HCl. The mixture was extracted with EA (10 mL x 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain the title compound as a colorless oil (50 mg, yield 78%). LCMS: 653.3(M+H) + .

[0601] Step 6: N-((5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)pyridine-2-yl)methyl)acetamide The title compound was prepared using tert-butyl 4-(2-(acetamidomethyl)-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate and TFA according to the procedure described for Example 368 to obtain the title compound (yield 6%). 1 H NMR (400 MHz, DMSO-d6): 8.42 (d, J = 1.6 Hz, 1H), 8.15-8.13 (m, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.56-7.54 (m, 1H), 7.47-7.45 (m, 1H), 7.24-7.19 (m, 2H), 4.47 (d, J = 5.2 Hz, 2H), 3.72 (t, J = 7.6 Hz, 2H), 3.49 (t, J = 8.0 Hz, 2H), 2.88-2.86 (m, 8H), 2.77 (s, 3H), 1.89 (s, 3H). No NH or OH protons were observed. LCMS: 553.3 (M + H) + .

[0602] Example 371 3-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)oxazolidine-2-one [ka]

[0603] Step 1: 3-(4-bromo-2-chlorophenyl)oxazolidine-2-one To a solution of 4-bromo-2-chloroaniline (1.00 g, 4.84 mmol) in MeOH (20 mL), 2-chloroethylcarbonochloride (692 mg, 4.84 mmol) and KOH (679 mg, 12.1 mmol) were added. After addition, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed by LC-MS, the reaction mixture was filtered, concentrated, diluted with H2O (50 mL), and extracted with EA (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (3:1) as eluents to obtain the title compound as a white solid (1.0 g, yield 76%). LC-MS: 275.9 (M + H) + .

[0604] Step 2: tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(2-oxoxazolidine-3-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 3-(4-bromo-2-chlorophenyl)oxazolidine-2-one and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 365, to obtain the title compound (yield 66%). LCMS: 583.2(M+H) + .

[0605] Step 3: 3-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)oxazolidine-2-one The title compound was prepared using tert-butyl 4-(4-(3'-chloro-5-fluoro-2-methoxy-4'-(2-oxoxazolidine-3-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 368, to obtain the title compound (yield 32%). 1 1H NMR (400 MHz, DMSO-d6): 8.18 (d, J = 6.8 Hz, 1H), 7.81 (s, 1H), 7.67-7.61 (m, 2H), 7.28-7.19 (m, 2H), 6.95 (s, 1H), 6.85 (d, J = 6.8 Hz, 1H), 4.55 (t, J = 9.6 Hz, 2H), 4.02 (t, J = 10.8 Hz, 2H), 3.50-3.46 (m, 4H), 2.84-2.81 (m, 4H). NH and OH protons were not observed. LCMS: 469.2 (M + H) + .

[0606] Example 372 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-3-(piperazine-1-yl)pyridine-2(1H)-one [ka]

[0607] Step 1: tert-butyl 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate To a solution of 3,5-dibromo-1-methylpyridine-2(1H)-one (267 mg, 1.00 mmol) and tert-butylpiperazine-1-carboxylate (186 mg, 1.00 mmol) in dioxane (10 mL), Cs2CO3 (652 mg, 2.00 mmol), Pd(dba)3 (91.6 mg, 0.100 mmol), and xanthophos (116 mg, 0.200 mmol) were added. After addition, the reaction mixture was stirred overnight at 110°C in a stale tube under a nitrogen atmosphere. After the reaction was completed by LC-MS, the reaction mixture was cooled and filtered. The filtrate was concentrated to obtain the residue, which was purified by silica gel chromatography using petroleum ether and ethyl acetate (4:1) as the eluent to obtain the title compound as a yellow solid (110 mg, yield 29%). LCMS:316.2(M-56+H) + .

[0608] Step 2: tert-butyl4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate and 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 342, yielding the title compound (59% yield). LCMS: 626.7(M+H) + .

[0609] Step 3: 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-3-(piperazine-1-yl)pyridine-2(1H)-one The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 342, to obtain the title compound (49% yield). 1 ¹H NMR (400 MHz, DMSO-d6): 7.71 (d, J = 2.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.14-7.10 (m, 2H), 6.85 (d, J = 2.0 Hz, 1H), 3.74-3.70 (m, 2H), 3.50-3.47 (m, 5H), 3.01 (s, 4H), 2.81-2.78 (m, 7H). NH and OH protons were not observed. LCMS: 512.3 (M + H) + .

[0610] Example 373 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)imidazolidined-2-one [ka]

[0611] Step 1: 1-(4-bromo-2-chlorophenyl)-3-(2-chloroethyl)urea A mixture of 4-bromo-2-chloroaniline (8.26 g, 40.1 mmol) and 1-chloro-2-isocyanatoethane (5.49 g, 52.0 mmol) in DCM (200 mL) was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was completed by LC-MS, the solvent was removed to obtain the residue, which was treated with toluene (50 mL), filtered, and the cake was dried to obtain the title compound as a gray solid (11.0 g, yield 88%). LC-MS: 311.1(M+H) + .

[0612] Step 2: 1-(4-bromo-2-chlorophenyl)imidazolidined-2-one To a solution of 1-(4-bromo-2-chlorophenyl)-3-(2-chloroethyl)urea (5.00 g, 16.0 mmol) in THF (75 mL), NaH (961 mg, 24.0 mmol, 60 wt% of mineral oil) was added. After addition, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was confirmed by LC-MS, the reaction mixture was quenched with H2O (110 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a pink solid (4.2 g, yield 95%). LC-MS: 275.0 (M + H) + .

[0613] Step 3: 1-Acetyl-3-(4-bromo-2-chlorophenyl)imidazolidined-2-one The reaction mixture was prepared by stirring overnight at 130°C in a solution of 1-(4-bromo-2-chlorophenyl)imidazolidined-2-one (500 mg, 1.81 mmol) in AC2O (10 mL). The reaction mixture was cooled, the solvent was removed, the residue was diluted with H2O (30 mL), the pH was adjusted to 9-11 with saturated K2CO3 aqueous solution, and the mixture was extracted with EA (30 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound as a brown solid (550 mg, yield 96%). LCMS: 317.1(M+H) + .

[0614] Step 4: tert-butyl4-(4-(4'-(3-acetyl-2-oxoimidazolidine-1-yl)-3'-chloro-5-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-acetyl-3-(4-bromo-2-chlorophenyl)imidazolidined-2-one and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 365, to obtain the title compound (42% yield). LCMS: 624.6(M+H) + .

[0615] Step 5: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)imidazolidined-2-one The title compound was prepared using tert-butyl 4-(4-(4'-(3-acetyl-2-oxoimidazolidine-1-yl)-3'-chloro-5-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 365, to obtain the title compound (30% yield). 1 1H NMR (400 MHz, DMSO-d6): 8.14 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 2.0, 8.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.21-7.15 (m, 2H), 6.91 (s, 1H), 6.84 (s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 3.80 (t, J = 7.2 Hz, 2H), 3.48-3.43 (m, 6H), 2.79-2.77 (m, 4H). No NH or OH protons were observed. LCMS: 468.2 (M + H) + .

[0616] Example 374 1-(3-chloro-3'-(2-ethyl-6-(piperazin-1-yl)pyridine-4-yl)-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0617] The title compound was prepared using tert-butyl 4-(6-chloro-4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and ethylboronic acid, following the procedure described for Example 368. 1 H NMR (400 MHz, DMSO-d6): 8.79-8.64 (m, 3H), 7.67 (d, J = 2.0 Hz, 1H), 7.51-7.44 (m, 2H), 7.33-7.26 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 3.75-3.70 (m, 6H), 3.49 (t, J = 6.0 Hz, 2H), 3.20 (s, 4H), 2.77 (s, 3H), 2.70-2.64 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H). LCMS: 492.2 (M + H) + .

[0618] Example 375 N-(3'-(2-((4-aminocyclohexyl)oxy)-6-(piperazine-1-yl)pyridine-4-yl)-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide [ka]

[0619] Step 1: tert-butyl 4-(6-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-4-iodopyridine-2-yl)piperazine-1-carboxylate To a suspension of tert-butyl (4-hydroxycyclohexyl)carbamate (951 mg, 4.42 mmol) in dioxane (20 mL), NaH (183 mg, 4.57 mmol, 60% in mineral oil) was gradually added. The reaction mixture was then stirred under nitrogen at room temperature for 15 minutes. Next, a solution of tert-butyl 4-(6-fluoro-4-iodopyridine-2-yl)piperazine-1-carboxylate (600 mg, 1.47 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred under nitrogen at 100 °C for 6 hours. After the reaction was complete by LC-MS, the reaction mixture was cooled, water (40 mL) was added, and it was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (50:1) and dichloromethane / methanol (1:1) as eluents to obtain the title compound as a white solid (55 mg, yield 5%). LCMS: 603.2(M+H) + .

[0620] Step 2: tert-butyl4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-6-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(6-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)-4-iodopyridine-2-yl)piperazine-1-carboxylate and N-(3-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)acetamide according to the procedure described for Example 163, yielding the title compound (89% yield). LCMS: 734.3(M+H) + .

[0621] Step 3: tert-butyl4-(4-(4'-acetamido-3'-fluoro-2-hydroxy-[1,1'-biphenyl]-3-yl)-6-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-6-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)pyridine-2-yl)piperazine-1-carboxylate and piperazine, following the procedure described for Example 163, to obtain the title compound (yield 28%). LCMS: 720.3(M+H) + .

[0622] Step 4: N-(3'-(2-((4-aminocyclohexyl)oxy)-6-(piperazine-1-yl)pyridine-4-yl)-3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)acetamide The title compound was prepared using tert-butyl 4-(4-(4'-acetamido-3'-fluoro-2-hydroxy-[1,1'-biphenyl]-3-yl)-6-((4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)pyridine-2-yl)piperazine-1-carboxylate and TFA, following the procedure described for Example 163, to obtain the title compound (80% yield). 11H NMR (400 MHz, CD3OD - bis TFA): 7.92 (t, J = 8.4 Hz, 1H), 7.39-7.24 (m, 4H), 7.03 (t, J = 7.6 Hz, 1H), 6.56 (s, 1H), 6.32 (s, 1H), 4.98-4.95 (m, 1H), 3.84-3.81 (m, 4H), 3.36-3.32 (m, 4H), 3.21-3.18 (m, 1H), 2.30-2.28 (m, 2H), 2.20 (s, 3H), 2.17-2.14 (m, 2H), 1.68-1.54 (m, 4H). No NH or OH protons were observed. LCMS: 520.3 (M + H) + .

[0623] Example 376 Methyl picolinate 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl) [ka]

[0624] Step 1: tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-2-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate and 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 368, yielding the title compound (59% yield). LCMS: 653.2(M+H) + .

[0625] Step 2: Methyl picolinate 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl) The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 368, to obtain the title compound (35% yield). 1 ¹H NMR (400 MHz, DMSO-d6): 8.35 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.62 (dd, J = 2.0, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.40-7.33 (m, 2H), 3.77-3.73 (m, 2H), 3.51-3.44 (m, 2H), 3.17-3.09 (m, 11H), 2.77 (s, 3H). NH and OH protons were not observed. LCMS: 540.0 (M + H) + .

[0626] Example 377 (R)-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-3-(3-methylpiperazine-1-yl)pyridine-2(1H)-one [ka]

[0627] The title compound was prepared using 3,5-dibromo-1-methylpyridine-2(1H)-one, (R)-tert-butyl2-methylpiperazine-1-carboxylate, 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one and BBr3, following the procedure described for Example 372, to obtain the title compound (15% yield). 1 H NMR (400 MHz, DMSO-d6): 7.70 (d, J = 2.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.15-7.10 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 3.74-3.70 (m, 2H), 3.58 (d, J = 11.2 Hz, 2H), 3.51-3.47 (m, 5H), 2.90-2.77 (m, 6H), 2.41-2.35 (m, 1H), 2.04 (t, J = 10.0 Hz, 1H), 0.97 (d, J = 6.4 Hz, 3H). No NH and OH protons were observed. LCMS: 526.3 (M + H) + .

[0628] Example 378 (S)-3-(3-aminopiperidine-1-yl)-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methylpyridine-2(1H)-one [ka]

[0629] The title compound was prepared using 3,5-dibromo-1-methylpyridine-2(1H)-one, (S)-tert-butylpiperidine-3-ylcarbamate, 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one and BBr3, following the procedure described for Example 372, to obtain the title compound (13% yield). 1 H NMR (400 MHz, DMSO-d6): 8.78 (s, 2H), 8.62 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.31 (dd, J = 2.0, 7.6 Hz, 1H), 7.26 (dd, J = 1.2, 7.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 3.74-7.68 (m, 6H), 3.48 (t, J = 8.0 Hz, 2H), 3.17 (s, 4H), 2.77 (s, 3H), 2.05-1.99 (m, 1H), 0.93-0.89 (m, 4H). LCMS: 504.2 (M + H) + .

[0630] Example 379 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(1',2',3',6'-tetrahydro-[2,4'-bipyridine]-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0631] Step 1: tert-butyl 4-chloro-5',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate The title compound was prepared using 2-bromo-4-chloropyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate according to the procedure described for Example 368, yielding the title compound (91% yield). LCMS: 239.1(M-56+H) + .

[0632] Step 2: tert-butyl4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-5',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate The title compound was prepared using tert-butyl 4-chloro-5',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 368, yielding the title compound (45% yield). LCMS: 593.6(M+H) + .

[0633] Step 3: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(1',2',3',6'-tetrahydro-[2,4'-bipyridine]-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-5',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate and BBr3 according to the procedure described for Example 368, and the title compound was obtained (yield 26%). 1H NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.44-7.42 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.15 (dd, J = 1.2, 8.4 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 3.89 (s, 2H), 3.74-3.70 (m, 2H), 3.48 (t, J = 8.0 Hz, 2H), 3.05 (t, J = 5.6 Hz, 2H), 2.77 (s, 3H), 2.72-2.67 (m, 2H). NH and OH protons were not observed. LCMS: 473.3 (M + H) + .

[0634] Example 380 1-(5'-fluoro-2'-hydroxy-3-methyl-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0635] Step 1: tert-butyl 4-(4-(5-fluoro-2-methoxy-3'-methyl-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-(4-bromo-2-methylphenyl)-3-methylimidazolidin-2-one and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 379, to obtain the title compound (yield 62%). LCMS: 576.7(M+H) + .

[0636] Step 2: 1-(5'-fluoro-2'-hydroxy-3-methyl-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(4-(5-fluoro-2-methoxy-3'-methyl-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 379, to obtain the title compound (yield 22%). 1 H NMR (400 MHz, DMSO-d6): 8.42 (d, J = 1.6 Hz, 1H), 8.15-8.13 (m, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.56-7.54 (m, 1H), 7.47-7.45 (m, 1H), 7.24-7.19 (m, 2H), 4.47 (d, J = 5.2 Hz, 2H), 3.72 (t, J = 7.6 Hz, 2H), 3.49 (t, J = 8.0 Hz, 2H), 2.88-2.86 (m, 8H), 2.77 (s, 3H), 1.89 (s, 3H). No NH or OH protons were observed. LCMS: 553.3 (M + H) + .

[0637] Example 381 1-Acetyl-3-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)imidazolidined-2-one [ka]

[0638] Step 1: tert-butyl4-(4-(4'-(3-acetyl-2-oxoimidazolidine-1-yl)-3'-chloro-5-fluoro-2-hydroxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-acetyl-3-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazolidin-2-one and tert-butyl-4-(4-(3-bromo-5-fluoro-2-hydroxyphenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 380, to obtain the title compound (78% yield). LCMS: 610.2(M+H) + .

[0639] Step 2: 1-Acetyl-3-(3-chloro-5'-fluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)imidazolidined-2-one The title compound was prepared using tert-butyl 4-(4-(4'-(3-acetyl-2-oxoimidazolidine-1-yl)-3'-chloro-5-fluoro-2-hydroxy-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and TFA according to the procedure described for Example 380, and the title compound was obtained (yield 62%). 1 1H NMR (400 MHz, DMSO-d6): 8.18 (d, J = 6.8 Hz, 1H), 7.81 (s, 1H), 7.67-7.61 (m, 2H), 7.28-7.19 (m, 2H), 6.95 (s, 1H), 6.85 (d, J = 6.8 Hz, 1H), 4.55 (t, J = 9.6 Hz, 2H), 4.02 (t, J = 10.8 Hz, 2H), 3.50-3.46 (m, 4H), 2.84-2.81 (m, 4H). NH and OH protons were not observed. LCMS: 469.2 (M + H) + .

[0640] Example 382 1-(3-chloro-3'-(6-ethyl-5-(piperazin-1-yl)pyridine-3-yl)-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0641] Step 1: tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-2-chloropyridine-3-yl)piperazine-1-carboxylate and 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one according to the procedure described for Example 374, yielding the title compound (61% yield). LCMS: 630.2(M+H) + .

[0642] Step 3: tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-ethylpyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate and ethylboronic acid, following the procedure described for Example 374, to obtain the title compound (yield 31%). LCMS: 624.7(M+H) + .

[0643] Step 4: 1-(3-chloro-3'-(6-ethyl-5-(piperazin-1-yl)pyridine-3-yl)-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-ethylpyridine-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 374, to obtain the title compound (yield 29%). 1 1H NMR (400 MHz, DMSO-d6): 8.39 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.56-7.54 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.23-7.17 (m, 2H), 3.75-7.30 (m, 2H), 3.51-3.47 (m, 2H), 2.93-2.92 (m, 4H), 2.86-2.80 (m, 6H), 2.77 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H). NH and OH protons were not observed. LCMS: 510.3 (M + H) + .

[0644] Example 383 N-(4-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-6-(piperazine-1-yl)pyridine-2-yl)acetamide [ka]

[0645] Step 1: tert-butyl 4-(6-acetamido-4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate A suspension of tert-butyl 4-(6-chloro-4-(3'-chloro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate (110 mg, 0.180 mmol), acetamide (32 mg, 0.54 mmol), xanthophos (13 mg, 0.022 mmol), K3PO4 (115 mg, 0.540 mmol), and Pd2(dba)3 (6.4 mg, 0.0070 mmol) in dioxane (2 mL) was stirred at 140 °C for 4 hours under a nitrogen atmosphere in a MW. After the reaction was completed by LC-MS, the reaction mixture was cooled and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate (10:1 to 1:3) as eluents to obtain the title compound as a yellow solid (80 mg, 70% yield). LCMS: 635.2(M+H) + .

[0646] Step 3: N-(4-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-6-(piperazine-1-yl)pyridine-2-yl)acetamide The title compound was prepared using tert-butyl 4-(6-acetamido-4-(3'-chloro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate according to the procedure described for Example 374, and the title compound was obtained (yield 49%). 1H NMR (400 MHz, DMSO-d6+D2O): 7.66 (d, J = 1.6 Hz, 1H), 7.57 (s, 1H), 7.51 (dd, J = 1.6, 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 2.0, 7.6 Hz, 1H), 7.24 (dd, J = 1.6, 7.6 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.71 (s, 1H), 3.76-3.71 (m, 6H), 3.48-3.47 (m, 2H), 3.20-3.18 (m, 4H), 2.77 (s, 3H), 2.09 (s, 3H). NH and OH protons were not observed. LCMS: 521.2 (M + H) + .

[0647] Example 384 1-Methyl-3-(3,5,5'-trifluoro-2'-hydroxy-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)imidazolidined-2-one [ka]

[0648] Step 1: tert-butyl 4-(4-(3',5,5'-trifluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate The title compound was prepared using 1-(4-bromo-2,6-difluorophenyl)-3-methylimidazolidin-2-one and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 380, to obtain the title compound (yield 51%). LCMS: 598.3(M+H) +

[0649] Step 2: 1-Methyl-3-(3,5,5'-trifluoro-2'-hydroxy-3'-(2-(piperazin-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)imidazolidined-2-one The title compound was prepared using tert-butyl 4-(4-(3',5,5'-trifluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-2-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 380, to obtain the title compound (35% yield). 1 1H NMR (400 MHz, DMSO-d6): 8.13 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 2H), 7.23 (dd, J = 3.2, 9.2 Hz, 1H), 7.18 (dd, J = 3.2, 9.2 Hz, 1H), 6.95 (s, 1H), 6.81 (dd, J = 1.2, 5.2 Hz, 1H), 3.69-3.65 (m, 2H), 3.54-3.50 (m, 2H), 3.44-3.42 (m, 4H), 2.79-2.76 (m, 7H). NH and OH protons were not observed. LCMS: 484.2 (M + H) + .

[0650] Example 385 1-(3-chloro-5'-fluoro-2'-hydroxy-5-methyl-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0651] The title compound was prepared using 4-bromo-2-chloro-6-methylaniline and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate according to the procedure described for Example 384, and the title compound was obtained (yield 9%). 1 1H NMR (400 MHz, DMSO-d6): 8.15 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.20-7.15 (m, 2H), 6.91 (s, 1H), 6.82 (d, J = 5.2 Hz, 1H), 3.71-3.65 (m, 4H), 3.58-3.53 (m, 4H), 2.82-2.79 (m, 4H), 2.75 (s, 3H), 2.69 (s, 3H). NH and OH protons were not observed. LCMS: 496.2 (M + H) + .

[0652] Example 386 1-(3-chloro-5'-fluoro-2'-hydroxy-5-methyl-3'-(2-(piperazine-1-yl)pyridine-4-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-one [ka]

[0653] The title compound was prepared using 1-(4-bromo-2-chloro-6-methylphenyl)pyrrolidine-2-one and tert-butyl 4-(4-(5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-2-yl)piperazine-1-carboxylate, following the procedure described for Example 252, to obtain the title compound (12% yield). 1H NMR (400 MHz, DMSO-d6): 8.14 (d, J = 5.2 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.21-7.15 (m, 2H), 6.91 (s, 1H), 6.81 (dd, J = 0.8, 5.2 Hz, 1H), 3.69-3.65 (m, 1H), 3.61-3.55 (m, 1H), 3.45-3.43 (m, 4H), 2.80-2.77 (m, 4H), 2.49-2.42 (m, 2H), 2.23 (s, 3H), 2.22-2.17 (m, (2H). No two NH or OH protons were observed. LCMS: 481.1 (M + H) + .

[0654] Example 387 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(hydroxymethyl)-5-(piperazine-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0655] Step 1: tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(hydroxymethyl)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-2-(hydroxymethyl)pyridine-3-yl)piperazine-1-carboxylate and 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one according to the procedure described for Example 376, yielding the title compound (34% yield). LCMS: 626.2(M+H)+ .

[0656] Step 2: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(hydroxymethyl)-5-(piperazin-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(hydroxymethyl)pyridine-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 376, to obtain the title compound (34% yield). 1 1H NMR (400 MHz, DMSO-d6): 8.41 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.58-7.54 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.25-7.19 (m, 2H), 5.03-5.01 (m, 1H), 4.61 (d, J = 4.8 Hz, 2H), 3.74-3.70 (m, 2H), 3.51-3.47 (m, 2H), 2.89-2.88 (m, 8H), 2.77 (s, 3H). NH and OH protons were not observed. LCMS: 512.3 (M + H) + .

[0657] Example 388 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-methyl-5-(piperazine-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0658] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate and methylboronic acid, following the procedure described for Example 382, ​​to obtain the title compound (yield 5%). 1 1H NMR (400 MHz, DMSO-d6): 8.29 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 2.0, 8.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.20-7.17 (m, 2H), 3.74-3.70 (m, 2H), 3.51-3.47 (m, 2H), 2.86-2.84 (m, 8H), 2.77 (s, 3H), 2.47 (s, 3H). No NH or OH protons were observed. LCMS: 496.2 (M + H) + .

[0659] Example 389 N-(5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)pyridine-2-yl)acetamide [ka]

[0660] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate and acetamide, following the procedure described for Example 383, to obtain the title compound (76% yield). 11H NMR (400 MHz, DMSO-d6): 9.20 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 2.0, 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.25-7.17 (m, 2H), 3.74-3.70 (m, 2H), 3.51-3.47 (m, 2H), 2.86-2.84 (m, 8H), 2.77 (s, 3H), 2.17 (s, 3H). No NH or OH protons were observed. LCMS: 539.1 (M + H) + .

[0661] Example 390 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(5-(piperazine-1-yl)-6-(1H-pyrazole-4-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0662] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate and BBr3, following the procedure described for Example 388, to obtain the title compound. 11H NMR (400 MHz, DMSO-d6-TFA salt): 8.86-8.75 (m, 3H), 8.51 (s, 1H), 8.41 (s, 2H), 7.79-7.73 (m, 2H), 7.56 (dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.32-7.22 (m, 2H), 3.75-3.71 (m, 2H), 3.51-3.47 (m, 2H), 3.34 (s, 4H), 3.10 (s, 4H), 2.77 (s, 3H). No NH or OH protons were observed. LCMS: 548.3 (M + H) + .

[0663] Example 391 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(5-(piperazine-1-yl)-6-(1H-pyrazole-5-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0664] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and BBr3, following the procedure described for Example 388, to obtain the title compound (14% yield). 1H NMR (400 MHz, DMSO-d6): 8.84-8.75 (m, 3H), 8.56 (d, J = 1.6 Hz 1H), 7.80 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.69 (s, 1H), 7.57 (dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 3.2, 8.8 Hz, 1H), 7.25 (dd, J = 2.8, 8.8 Hz, 1H), 7.07 (s, 1H), 3.96-3.94 (m, 2H), 3.75-3.71 (m, 2H), 3.33 (s, 4H), 3.13 (s, 4H), 2.77 (s, 3H). No NH or OH protons were observed. LCMS: 548.3 (M + H) + .

[0665] Example 392 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(2-hydroxyethoxy)-5-(piperazine-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0666] Step 1: tert-butyl4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(2-methoxyethoxy)pyridine-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate (200 mg, 0.317 mmol) in dioxane (10 mL), 2-methoxyethanol (121 mg, 1.59 mmol) and NaH (76.1 mg, 3.17 mmol, 60% in mineral oil) were added. After stirring at 100°C for 12 hours, the reaction mixture was cooled, 20 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the residue, which was purified by silica gel chromatography using petroleum ether and ethyl acetate (1:1) as the eluent to obtain the title compound as a yellow solid (160 mg, yield 79%). LCMS: 670.7 (M+H) + .

[0667] Step 2: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(2-hydroxyethoxy)-5-(piperazin-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(2-methoxyethoxy)pyridine-3-yl)piperazine-1-carboxylate and BBr3 according to the procedure described for Example 388 (12% yield). 1H NMR (400 MHz, DMSO-d6): 7.86 (d, J = 2.4 Hz 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 2.0, 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.18-7.13 (m, 2H), 4.79-4.76 (m, 1H), 4.36 (t, J = 4.8 Hz, 2H), 3.76-3.70 (m, 4H), 3.50-3.46 (m, 2H), 3.02-2.97 (m, 4H), 2.84-2.83 (m, 4H), 2.77 (s, 3H). NH and OH protons were not observed. LCMS: 542.3 (M + H) + .

[0668] Example 393 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(2-methoxyethoxy)-5-(piperazine-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0669] The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(2-methoxyethoxy)pyridine-3-yl)piperazine-1-carboxylate and TFA according to the procedure described for Example 392 (yield 25%). 1H NMR (400 MHz, DMSO-d6): 7.86 (d, J = 2.0 Hz 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 1.6, 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.18-7.13 (m, 2H), 4.44 (t, J = 4.8 Hz, 2H), 3.74-3.69 (m, 4H), 3.50-3.46 (m, 2H), 3.33 (s, 3H), 3.02-2.97 (m, 4H), 2.84-2.83 (m, 4H), 2.77 (s, 3H). No NH and OH protons were observed. LCMS: 556.3 (M + H) + .

[0670] Example 394 (S)-3-(3-aminopyrrolidine-1-yl)-5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-1-methylpyridine-2(1H)-one [ka]

[0671] The title compound was prepared using (S)-tert-butyl(1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-yl)pyrrolidine-3-yl)carbamate, 1-(3-chloro-5'-fluoro-2'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidin-2-one and BBr3, following the procedure described for Example 378, to obtain the title compound. 1H NMR (400 MHz, DMSO-d6+D2O): 7.71 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 2.0, 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 6.69 (d, J = 2.0 Hz, 1H), 3.84-3.81 (m, 1H), 3.76-3.72 (m, 2H), 3.63-3.50 (m, 8H), 3.24-3.21 (m, 1H), 2.78 (s, 3H), 2.32-2.28 (m, 1H), 1.96–1.90 (m, 1H). NH and OH protons were not observed. LCMS: 512.2 (M + H) + .

[0672] Example 395 N-(2-((5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)pyridine-2-yl)amino)ethyl)acetamide [ka]

[0673] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate, N-(2-aminoethyl)acetamide, and BBr3 according to the procedure described in Example 393 to obtain the title compound (32% yield). 1H NMR (400 MHz, DMSO-d6): 8.00 (t, J = 5.2 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 2.0, 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.11-7.06 (m, 2H), 6.00 (t, J = 5.6 Hz, 1H), 3.74-3.70 (m, 2H), 3.51-3.42 (m, 4H), 3.31-3.28 (m, 2H), 2.88–2.87 (m, 4H), 2.77 (s, 3H), 2.73 (s, 4H), 1.82 (s, 3H). NH and OH protons were not observed. LCMS: 582.1 (M + H) + .

[0674] Example 396 N-(2-((5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)pyridine-2-yl)oxy)ethyl)acetamide [ka]

[0675] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate, N-(2-hydroxyethyl)acetamide, piperazine, and TFA, following the procedure described for Example 395, to obtain the title compound (yield 35%). 11H NMR (400 MHz, DMSO-d6+D2O): 7.96 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 1.6, 8.4 Hz, 1H), 7.48-7.45 (m, 2H), 7.19-7.15 (m, 2H), 4.35-4.28 (m, 2H), 3.79-3.75 (m, 2H), 3.59-3.53 (m, 4H), 3.30 (s, 8H), 2.80 (s, 3H), 1.92 (s, 3H). NH and OH protons were not observed. LCMS: 583.1 (M + H) + .

[0676] Example 397 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(5-(piperazine-1-yl)-6-(pyrrolidine-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0677] The title compound was prepared using tert-butyl 4-(2-chloro-5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)pyridine-3-yl)piperazine-1-carboxylate, pyrrolidine, and BBr3, following the procedure described for Example 395. 11H NMR (400 MHz, DMSO-d6+D2O): 7.95 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.54 (dd, J = 1.2, 8.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.28-7.21 (m, 2H), 3.80-3.73 (m, 6H), 3.54-3.50 (m, 2H), 3.31 (s, 4H), 3.13 (s, 4H), 2.78 (s, 3H), 1.99 (s, 4H). No NH or OH protons were observed. LCMS: 551.3 (M + H) + .

[0678] Example 398 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)picolinic acid [ka]

[0679] Step 1: Methyl picolinate 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl) The title compound was prepared using tert-butyl 4-(5-(3'-chloro-5-fluoro-2-methoxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate and BBr3, following the procedure described for Example 376, to obtain the title compound (quantitatively). LCMS: 540.1(M+H) +

[0680] Step 2: 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl)picolinic acid A mixture of methyl 5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-3-(piperazine-1-yl) (18 mg, 0.033 mmol) and LiOH·H2O (5.5 mg, 0.13 mmol) in 3 mL of THF / MeOH / H2O (1:1:1) was stirred at room temperature for 4 hours. The reaction mixture was dried under reduced pressure. The product was purified by preparative HPLC to obtain the title compound as a yellow solid (0.92 mg, yield 5%). 1 ¹H NMR (400 MHz, CD3OD): 7.70 (s, 1H), 7.12 (s, 1H), 6.91 (d, J = 4.0 Hz, 1H), 6.73 (dd, J = 2.0, 7.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.42-6.32 (m, 2H), 3.05-3.01 (m, 2H), 2.80 (t, J = 8.8 Hz, 2H), 2.56 (s, 8H), 2.09 (s, 3H). NH and OH protons were not observed. LCMS: 526.2 (M + H) + .

[0681] Example 399 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(methoxymethyl)-5-(piperazine-1-yl)pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one [ka]

[0682] Step 1: tert-butyl 4-(5-bromo-2-(hydroxymethyl)pyridine-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(5-bromo-2-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate (800 mg, 2.00 mmol), CaCl2 (1.11 g, 10.0 mmol), and NaBH4 (371 mg, 10.0 mmol) in 20 mL of CH3OH / THF (1:1) was stirred at 0°C for 4 hours. After the reaction was completed by LC-MS, the reaction mixture was concentrated to obtain the residue, which was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the title compound as a white solid (464 mg, yield 63%). LC-MS: 374.1(M+H) + .

[0683] Step 2: tert-butyl 4-(5-bromo-2-(methoxymethyl)pyridine-3-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-bromo-2-(hydroxymethyl)pyridine-3-yl)piperazine-1-carboxylate (300 mg, 0.809 mmol) in DMF (10 mL), NaH (58.2 mg, 2.43 mmol, 60 wt% in mineral oil) was added at 0°C. After stirring at 0°C for 30 minutes, CH3I (230 mg, 1.62 mmol) was added. The reaction mixture was stirred at room temperature for a further 2.5 hours under an N2 atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with EA (15 mL x 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the title compound as a yellow solid (212 mg, yield 68%). LCMS: 388.1(M+H) + .

[0684] Step 3: tert-butyl 4-(2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(5-bromo-2-(methoxymethyl)pyridine-3-yl)piperazine-1-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) according to the procedure described for Example 398, and the title compound (quantitative) was obtained. LCMS: 434.2(M+H) + .

[0685] Step 4: tert-butyl4-(5-(3'-chloro-5-fluoro-2-hydroxy-4'-(3-methyl-2-oxoimidazolidine-1-yl)-[1,1'-biphenyl]-3-yl)-2-(methoxymethyl)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared using tert-butyl 4-(2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)piperazine-1-carboxylate and 1-(3'-bromo-3-chloro-5'-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)-3-methylimidazolidined-2-one according to the procedure described for Example 398, yielding the title compound (58% yield). LCMS: 626.2(M+H) + .

[0686] Step 5: 1-(3-chloro-5'-fluoro-2'-hydroxy-3'-(6-(methoxymethyl)-5-(piperaz...

Claims

1. Compounds having the structure of formula (XI), or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, K7 is N or CH; Ring C represents a substituted or unsubstituted arylene or a heteroarylene; R １ and R ｘ Together with the intervening atom, it forms a heterocycloalkyl ring, heterocycloalkenyl ring, or heteroaryl ring, which may be substituted; R ａ Each entity is Halo, -NH ２ -NH (alkyl), -NH (cycloalkyl), -N (alkyl) ２ Independently selected from the group consisting of hydroxyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, haloalkoxy, heterocycloalkoxy, cyano, aryloxy, heteroaryloxy, and haloalkyl; J represents -OH, -O(alkyl), -OC(O)(alkyl), -OC(O)O(alkyl), -OC(O)NH(alkyl), -OC(O)N(alkyl) ２ , -OCH ２ OC(O)O(alkyl), -NH ２ , -NHR ｊ , or -CHF ２ ; R ｊ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R ｂ The presence of each of these includes halo, oxo, alkyl, alkoxy, haloalkyl, cyano, cycloalkyl, aryl, aryloxy, -OH, -NH(alkyl), -C(O)H, and -CO ２ (Alkyl), and -CO ２ Independently selected from the group consisting of H; R ｃ represents a heterocycloalkyl, cycloalkyl, alkyl, aryl, heteroaryl, (heterocycloalkyl)alkyl, heterocycloalkenyl, alkoxy, alkynyl, aryloxy, haloalkyl, haloalkoxy, cycloalkoxy, or heterocycloalkoxy, or halo, -S(alkyl), -NH ２ , -CO ２ H, -CO ２ (Alkyl) or -NHCO(Alkyl) represents; R ｉ Each of these is present as halo, oxo, -S (alkyl), -NH ２ -NH (alkyl), -N (alkyl) ２ Independently selected from the group consisting of alkyl, haloalkyl, haloalkoxyl, alkoxyl, heterocycloalkyl, and cycloalkoxyl groups, which may be -OH, cyano, or optionally substituted; Alternatively, R ｃ and R ｉ The presence of the intervening atom, together with the intervening atom, forms an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring which may be optionally substituted; Alternatively, R ｉ The presence of two adjacent atoms, together with the intervening atom, forms an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring which may be optionally substituted; m, n, and p are each independently 0, 1, or 2.

2. (A) Formula (XIb): 【Chemistry 2】 Having a structure, or (B) Formula (XIbh): 【Transformation 3】 Having a structure, or (C) Formula (XIcm): 【Chemistry 4】 [In the formula, X and Y are each independently selected from CH and N, and at least one of X and Y is CH.] Having a structure, or (D) Formula (XIcp): 【Transformation 5】 [In the formula, X and Y are each independently selected from CH and N, and at least one of X and Y is CH.] Having a structure, or (E) Formula (XIco): 【Transformation 6】 [In the formula, X and Y are each independently selected from CH and N, and at least one of X and Y is CH.] The compound according to claim 1, having the structure.

3. (A) Equation (XIai) or Equation (XIaii): 【Transformation 7】 【Transformation 8】 Having a structure, or (B) Formula (XIbi), formula (XIbii), or formula (XIbiiii): 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 Having a structure, or (C) Formula (XIbhii), formula (XIbhiiii), or formula (XIbhiv): 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 Having a structure, or (D) Formula (XIcmi), formula (XIcmii), or formula (XIcmiiii): 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 Having a structure, or (E) Equation (Xicp), Equation (Xicpii), or Equation (Xicpiii): [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 Having a structure, or (F) Formula (XIcoi), formula (XIcoii), or formula (XIcoiiii): 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 The compound according to claim 1, having the structure.

4. (G) Formula (Ie) or formula (Ieu): 【Chemistry 24】 【Chemistry 25】 [In the formula, X and Y are each independently selected from CH and N, and at least one of X and Y is CH.] Having a structure, or (H) Equation (If) or Equation (Ifu): 【Chemistry 26】 【Chemistry 27】 [In the formula, X and Y are each independently selected from CH and N, and at least one of X and Y is CH.] The compound according to claim 1, having the structure.

5. (G) Formula (Iei), Formula (Ieiii), or Formula (Ieiiii): 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 Having a structure, or (H) Formula (Ifi), Formula (Ifii), or Formula (Ifiii): 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 The compound according to claim 4, having the structure.

6. (I) Equation (XIgi) or Equation (XIgia): 【Transformation 34】 【Chemistry 35】 Having a structure, or (J) Formula (XIgii): 【Transformation 36】 Having a structure, or (K) Formula (XIgiiii) or formula (XIgiia): 【Chemistry 37】 【Transformation 38】 The compound according to claim 1, having the structure.

7. (I) Equation (Igib): 【Chemistry 39】 Having a structure, or (J) Formula (Igia): 【Chemistry 40】 Having a structure, or (K) Formula (Igiiib): 【Chemistry 41】 The compound according to claim 1, having the structure.

8. (i) 【Chemistry 42】 teeth, 【Chemistry 43】 Selected from the group consisting of, (ii) 【Chemistry 44】 teeth, 【Chemistry 45】 Selected from the group consisting of, (iii) 【Chemistry 46】 teeth, 【Chemistry 47】 Selected from the group consisting of, (iv) 【Chemistry 48】 teeth, 【Chemistry 49】 A compound according to claim 1, selected from the group consisting of the following.

9. J is -OH or -NH ２ The compound according to claim 1, which represents the compound described in claim 1.

10. The compound according to claim 1, wherein J represents -OH.

11. (i) n is 0, or (ii) n is 1, R ｂ The compound according to claim 1, wherein is a halo or methyl.

12. n is 1, R ｂ The compound according to claim 11, wherein is a halo.

13. R ｂ The compound according to claim 12, wherein is fluoro.

14. (i) p is 0, or (ii) p is 1, R ｉ The compound according to claim 1, wherein is alkyl or alkoxyl.

15. R ｃ The compound according to claim 1, wherein is optionally substituted with a heterocycloalkyl group.

16. R ｃ The compound according to claim 1, wherein is optionally substituted with piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azepanil, 3,8-diazabicyclo[3.2.1]octanil, or 2,6-diazaspiro[3.3]heptanil.

17. R ｃ The compound according to claim 1, wherein represents piperazinyl, piperidinyl, or pyrrolidinyl, each of which may be optionally substituted with one or more substituents selected from the group consisting of amino, alkylamino, aminoalkyl, alkyl, alkoxyalkyl, halo, oxo, hydroxyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, amide, and alkoxyl.

18. R ｃ The compound according to claim 1, wherein is an alkyl-substituted piperazinyl.

19. R ｃ teeth, [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 A compound according to claim 1, selected from the group consisting of the following.

20. (i) Compounds in the following table: Table 1 Selected from, (ii) Compounds in the following table: Table 2-1 Table 2-2 Selected from, (iii) Compounds in the following table: Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Selected from, (iv) Compounds in the table below: Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Selected from, (v) Compounds in the following table: Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 5-12 Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Selected from, (vi) Compounds in the following table: Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 6-7 Table 6-8 Table 6-9 Table 6-10 Table 6-11 Table 6-12 Table 6-13 Table 6-14 Table 6-15 Table 6-16 Selected from, (vii) Compounds in the following table: Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Table 7-16 Table 7-17 Selected from, (viiii) Compounds in the following table: Table 8-1 Table 8-2 Table 8-3 Table 8-4 Table 8-5 Table 8-6 Table 8-7 Table 8-8 Table 8-9 Table 8-10 Table 8-11 Table 8-12 Table 8-13 Table 8-14 Table 8-15 Selected from, (ix) Compounds in the table below: Table 9-1 Table 9-2 Table 9-3 Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 A compound according to claim 1, selected from the following.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

22. A composition for treating or preventing cancer, comprising a compound according to any one of claims 1 to 20.

23. The aforementioned cancers include acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, myelomonocytic, and promyelocytic), acute T-cell leukemia, adrenocortical carcinoma, anal cancer, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain tumor, breast cancer, bronchogenic carcinoma, carcinosarcoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. Granulocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, clear cell carcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, fibrinogenic round cell tumor, diffuse large B-cell lymphoma, proliferative abnormalities (dysplasia and metaplasia), fetal cancer, endometrial cancer, endoplasmosis, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential erythrombosis Ipathemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, gallbladder cancer, gastric cancer, testicular germ cell tumor, glioma, glioblastoma, gliosarcoma, hairy cell leukemia, heavy chain disease, hemangioblastoma, liver cancer (hepatoma), hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, lipogenic sarcoma, lymphoma, malignant peripheral nerve sheath tumor, medullary carcinoma, mantle cell lymphoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma. The composition according to claim 22, selected from the group consisting of myelodysplastic syndrome, myeloproliferative disorders, myelofibrosis, mucoepidermoid carcinoma, myxoid neoplasm, myxosarcoma, neuroblastoma, NUT midline carcinoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pheochromocytoma, pineal glandoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, reticulum sarcoma, retinoblastoma, rhabdomyosarcoma, salivary ductal carcinoma, sebaceous gland carcinoma, seminomas, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), squamous cell carcinoma, synovial sarcoma, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumor, endometrial cancer, and Wilms' tumor.

24. A composition for treating a disease or condition, comprising a compound according to any one of claims 1 to 20, (i) The diseases or conditions mentioned above include Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behçet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, dermatomyositis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, juvenile arthritis, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, and pancreatitis. Selected from the group consisting of childhood inflammatory multiple system syndrome, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, scleroderma, sclerosing cholangitis, sepsis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, Takayasu's arteritis, toxic shock syndrome, thyroiditis, type 1 diabetes mellitus, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis, or (ii) A composition in which the disease or condition is selected from the group consisting of obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes mellitus, insulin resistance, diabetic retinopathy, and diabetic neuropathy.

25. A composition for treating acquired immunodeficiency syndrome (AIDS), fibrosis, or epithelial wounds, comprising a compound according to any one of claims 1 to 20.

26. The composition according to claim 25, wherein the fibrosis is pulmonary fibrosis, renal fibrosis, hepatic fibrosis, or cardiac fibrosis, and the epithelial wound is a surgical wound, burn, abrasion, ulcer, or diabetic wound, wound caused by cancer, wound caused by an infectious disease, or wound caused by an inflammatory disease.

27. A composition for treating acute kidney disease, comprising a compound according to any one of claims 1 to 20, wherein the acute kidney disease or condition is selected from the group consisting of ischemia-reperfusion-induced kidney disease, cardiac and major surgery-induced kidney disease, percutaneous coronary intervention-induced kidney disease, contrast agent-induced kidney disease, sepsis-induced kidney disease, pneumonia-induced kidney disease, drug toxicity-induced kidney disease, diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubulointerstitial nephritis.

28. A composition for treating a viral infection, comprising a compound according to any one of claims 1 to 20, wherein the viral infection is caused by a DNA virus or an RNA virus.

29. (i) The viral infection is caused by a DNA virus selected from the group of viridae families consisting of Adenoviridae, Papovaviridae, Parvoviridae, Herpesviridae, Poxviridae, Anelloviridae, and Pleolipoviridae, or (ii) The aforementioned viral infections include those of the Reovirida, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Bunyaviridae families. The composition according to claim 28, which is caused by an RNA virus selected from the following virological families: yaviridae, rhabdoviridae, filoviridae, coronavirusidae, astroviridae, bornaviridae, arteriviridae, and hepeviridae.

30. The composition according to claim 28, wherein the viral infection is caused by an RNA virus of the Coronaviridae family.

31. The composition according to claim 30, wherein the viral infection is SARS-CoV or SARS-CoV-2.

32. A composition for selectively inhibiting bromodomain and extraterminal (BET) proteins in cells at the bromodomain II (BDII) level, comprising a compound according to any one of claims 1 to 20, wherein the compound is brought into contact with a cell.

33. The composition according to claim 32, wherein the cells are located in the body of a mammal or in the body of a human.

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